ES2609980T3 - Procedure to produce pyrrole compound - Google Patents

Abstract

A method of producing a compound represented by the formula ** Formula ** wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R2 5 is a hydrogen atom, an optionally substituted alkyl group, an acyl group , an optionally substituted hydroxy group, an optionally substituted amino group, a chlorine atom or a fluorine atom, or a salt thereof, which comprises reducing a compound represented by the formula ** Formula ** wherein each symbol is according to defined above, or a salt thereof, and hydrolyze the reduced product.

Description

DESCRIPTION

Procedure to produce pyrrole compound Technical field

The present invention relates to a method of producing a pyrrole compound useful as a pharmaceutical product, in particular an acid secretion inhibitor, and to a method of producing an intermediate product used for the present method.

Background of the invention

A pyrrole compound having a substituted sulfonyl group at position 1 (mentioned below as a sulfonylpyrrole compound), is useful as an acid secretion inhibitor (proton pump inhibitor), a therapeutic drug for a neoplastic disease or an autoimmune disease (patent documents 1-3).

For example, patent document 2 describes, as a compound having acid secretion suppressing activity, a compound represented by the formula:

image 1

Wherein r1 is a heterodyl group containing monodyl nitrogen, optionally condensed with a benzene ring or a heterocycle, wherein the heterodyl group containing monodyl nitrogen optionally fused with a benzene ring or a heterocycle optionally has substituent (s), R2 is an optionally substituted C6-14 aryl group, an optionally substituted thienyl group or an optionally substituted pyridyl group, R3 and R4 are each a hydrogen atom, or one of R3 and R4 is a hydrogen atom and the other is an optionally substituted lower alkyl group, an acyl group, a halogen atom, a cyano group or a nitro group, and r5 is an alkyl group, or a salt thereof.

Patent document 2 describes, as a method of producing a sulfonylpyrrole compound, the following method using a pyrrole-3-carboxylate:

image2

image3

Patent document 3 describes the following production method of a sulfonylpyrrole compound:

image4

5 On the other hand, the following method is known as the production method of a 2-halogen-3-cyanopyrrole compound.

Patent Document 4

image5

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As the method for the production of a 3-cyanopyrrole compound from a 2-halogen-3-cyanopyrrole compound, the following methods are known.

Non-patent document 1, non-patent document 2:

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As the method for the production of a 3-formylpyrrole compound from a 3-cyanopyrrole compound, the following methods are known.

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Non-patent document 4

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Patent Document 5

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In addition, as the 3-cyanopyrrole compound, the following compounds are known.

Patent Document 6

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5

Patent Document 7

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Table 1

 Wa

 Xa Ya za R3

 3-CN

 4-Cl 5-Cl 2- (p (CF3O-CaH5) C2H5

 4-NO2

 2-Br 3-Br 5- (p-Cl-CaH5) C2H5

 4-NO2

 2-Cl 3-Cl 5- (3,4-diCl-CaH5) C2H5

 4-NO2

 2-Cl 3-Cl 5- (p-Br-CaH5) C2H5

 e-CN

 4-Cl 5-Cl 2- (p-CF3-CaH5) C2H5

 3-CN

 4-Cl 5-Cl 2- (3,4-diCl-CaH5) C2H5

 3-CN

 4-Cl 5-Cl 2- (p-Cl-CaH5) C2H5

 4-NO2

 2- (p-Cl-CaH5) 5-CF3 2- (p-Cl-CaH5) C2H5

 3-CN

 4-Br 5-Br 2-Br C2H5

 3-CN

 4-Br 5-CF3 2- (p-Cl-CaH5) C2H5

 3-CN

 4-Cl 5-CF3 2- (p-Cl-CaH5) C2H5

 4-NO2

 3- (p-Cl-CaH5) 5-CF3 2- (p-Cl-CaH5) C2H5

 4-NO2

 4- (3,4-diCl-CaH5) 5-CF3 2- (p-Cl-CaH5) C2H5

 4-NO2

 3- (m-CN-CaH5) 2-CF3 5- (p-Cl-CaH5) C2H5

 3-CN

 4-Br 5-Br 2- (p-CF3-CaH5) C2H5

 3-CN

 2-Cl 4-Cl 5- (3,4-diCl-CaH5) C2H5

 3-CN

 2-Cl 4-Br 5- (p-Br-CaH5) C2H5

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Patent Document 8

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Patent Document 9

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Patent Document 10

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Table 2

 Compound No.

 Qn xb Yb zb

 2-5

 3-Cl H CN H

 2-6

 3-Cl CH3 CN H

 2-7

 3-Cl Cl CN H

 2-8

 3-Cl Br CN H

 2-31

 3-Cl H CN CH3

 2-32

 3-Cl H CN CHO

 2-57

 3-Me H CN H

 2-58

 3-Me CH3 CN H

 2-59

 3-Me Cl CN H

 2-60

 3-Me Br CN H

 2-72

 3-Me H CN CH3

 2-73

 3-Me H CN CHO

 2-92

 3-cyclopropyl H CN H

 2-93

 3-cyclopropyl CH3 CN H

 2-94

 3-cyclopropyl Cl CN H

 2-95

 3-cyclopropyl Br CN H

 2-108

 3-cyclopropyl H CN CH3

 2-109

 3-cyclopropyl H CN CHO

Table 3

 Compound No.

 Qn Xb Yb Zb

 2-128

 5-cyclopropyl H CN H

 2-129

 5-cyclopropyl CH3 CN H

 2-130

 5-cyclopropyl Cl CN H

 2-131

 5-cyclopropyl Br CN H

 2-145

 5-cyclopropyl H CN CH3

 2-146

 5-cyclopropyl H CN CHO

 2-157

 5-Et H CN H

 2-158

 5-Et CH3 CN H

 2-159

 5-Et Cl CN H

 2-160

 5-Et Br CN H

 2-175

 5-Et H CN CH3

 2-176

 5-Et H CN CHO

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 2-195

 3-CECH H CN H

 2-196

 3-CECH CH3 CN H

 2-197

 3-CECH Cl CN H

 2-198

 3-CECH Br CN H

 2-212

 3-CECH H CN CH3

 2-213

 3-CECH H CN CHO

Additionally, as the 2-mercaptopyrrole derivative, the following compounds are known.

For example, non-patent document 5 describes the derivative (A) of 2-mercaptopyrrole having a cyano group in position 3:

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Non-patent document 6 describes the derivative (B) of 2-mercaptopyrrole having a cyano group in position 3:

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Patent document 11 describes the derivative (C) of 2-mercaptopyrrole having a cyano group in position 3:

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(D) 2-mercaptopyrrole that has a cyano group in position 3:

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As a method of synthesis of these 2-mercaptopyrrole derivatives having a cyano group in position 3, the non-patent document 5 describes, as shown in the reaction scheme that follows, a method of synthesis of the derivative (A) of mercaptopyrrole by a reaction of a derivative of (2-oxoethyl) malononitrile with hydrogen sulfide; however, no desulfurization reaction is described.

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Additionally, non-patent document 6 describes, as shown in the reaction scheme that follows, a method of synthesis of the derivative (B) of 2-mercaptopyrrole having a cyano group in position 3; however, it is not by a ring closure reaction of a derivative of (2-oxoethyl) malononitrile and a sulfur compound. In addition, no desulfurization reaction of the 2-mercaptopyrrole derivative obtained is described.

image22

In addition, patent document 11 describes, as shown in the reaction scheme that follows, a 2-mercaptopyrrole derivative (c) synthesis method having a cyano group at position 3; however, it is not by a ring closure reaction of a derivative of (2-oxoethyl) malononitrile and a sulfur compound. In addition, no desulfurization reaction of the 2-mercaptopyrrole derivative obtained is described.

image23

In addition, patent document 12 describes, as shown in the reaction scheme that follows, a method of synthesis of the derivative (D) of 2-mercaptopyrrole having a cyano group at position 3; however, it is not by a ring closure reaction of a derivative of (2-oxoethyl) malononitrile and a sulfur compound. Additionally, no desulfurization reaction of the 2-mercaptopyrrole derivative obtained is described.

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Patent documents

Patent document 1: WO2006 / 036024 Patent document 2: WO2007 / 026916

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Patent document 3: WO2004 / 103968 Patent document 4: JP-A-6-9554 Patent document 5: US patent no. 4,904,687 Patent document 6: EP-A-358047 Patent document 7: EP-A-491136 Patent document 8: US patent no. 5,359,090 Patent document 9: US patent no. 5,563,279 Patent document 10: JP-A-10-324687 Patent document 11: WO 2005/040110 Patent document 12: WO2006 / 064944 Non-patent documents

Non-patent document 1: J. Med. Chem., 1995, 38 (12), 2158-2165 Non-patent document 2: Nucleosides Nucleotides, 1997, 16 (7-9), 941-944 Non-patent document 3: J. Med. Chem., 1995, 38 (20), 4106-4144 Non-patent document 4: Can. J. Chem., 1980, 58, 409-411

Non-patent document 5: Chemistry Heterocyclic Compound, 1992, vol. 2, page 277 Non-patent document 6: Tetrahedron, 1991, vol. 47, page 8243 Summary of the invention

A more efficient method of producing a sulfonylpyrrole compound useful as a pharmaceutical product is desirable. In addition, the preparation of an intermediate product used for this method is desired.

The inventors of the present have intensively studied a method of producing a sulfonylpyrrole compound useful as an acid secretion inhibitor, in particular a compound represented by the formula (VIII):

image25

wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterodyl group, R2 is a hydrogen atom, an optionally substituted alkyl group, an acyl group, an optionally substituted hydroxy group, an optionally substituted amino group, a chlorine atom or a fluorine atom, R3 is an optionally substituted hydrocarbon group or an optionally substituted heterodyl group, and R4 is an alkyl group, or a salt thereof. As a result, they have found a novel method of producing a sulfonylpyrrole compound, which uses a 3-cyanopyrrole compound of formula (III).

Accordingly, the present invention relates to the following invention: (1) a method of producing a compound represented by the formula

image26

wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterodyl group, and R2 is a hydrogen atom, an optionally substituted alkyl group, an acyl group, a hydroxy group

optionally substituted, an optionally substituted amino group, a chlorine atom or a fluorine atom, or a salt thereof, which comprises the reduction of a compound represented by the formula

image27

wherein each symbol is as previously defined, or a salt thereof, and the hydrolysis of the product 10 reduced, and

(2) a method of producing a compound represented by the formula

image28

wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterodyl group, R2 is a hydrogen atom, an optionally substituted alkyl group, an acyl group, an optionally substituted hydroxy group, an optionally substituted amino group, a chlorine atom or a fluorine atom, R3 is an optionally substituted hydrocarbon group or an optionally substituted heterodyl group, and R4 is an alkyl group, or a salt thereof, comprising:

(I) reduce a compound represented by the formula

image29

wherein each symbol is as defined above, or a salt thereof, and hydrolyzed the reduced product to obtain a compound represented by the formula

image30

where each symbol is as previously defined, or a salt thereof,

5 (II) react the compound obtained with a compound represented by the formula:

R3-SO2-X (V)

wherein R3 is as defined above, and X is a labile group, or a salt thereof, to provide a compound represented by the formula

image31

10 where each symbol is as previously defined, or a salt thereof, and

(III) reacting the compound obtained with a compound represented by the formula:

R4-NH2 (VII)

wherein R4 is as previously defined, or a salt thereof, in the presence of a reducing agent. Effect of the invention

According to the method of the present invention, since a sulfonylpyrrole compound is obtained in a short stage compared to conventional methods, the sulfonylpyrrole compound can be produced at low cost.

The present invention relates to a method of producing a sulfonylpyrrole compound useful as an acid secretion inhibitor, in particular a compound represented by the formula (VIII):

image32

Wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterodyl group, R2 is a hydrogen atom, an optionally substituted alkyl group, an acyl group, an optionally substituted hydroxy group, an optionally substituted amino group, a chlorine atom or a fluorine atom, R3 is a

optionally substituted hydrocarbon group or an optionally substituted heterodyl group, and R4 is an alkyl group (which is sometimes abbreviated as compound (VIII)) or a salt thereof, a method of producing an intermediate product for the same . The compound (VIII) or a salt thereof, shows a highly intense inhibitory effect of proton pump. Since compound VIII, or a salt thereof, inhibits the reversibly proton pump activity (H + / K + -ATPase) and in a K + antagonistic inhibitory manner to consequently suppress acid secretion, it is sometimes referred to as a blocker. of competitive potassium acid: P-CAB or as an acid pump antagonist (APA). The compound (VIII), or a salt thereof, quickly expresses action, and shows maximum efficiency from the initial administration. In addition, it is characterized by a small influence of metabolism polymorphisms (dispersion among patients), low cytotoxicity, weak inhibitory activity of cytochrome P450 (CYP) and hERG inhibitory activity, and long duration of its action. Therefore, the compound (VIII), or a salt thereof, obtained according to the method of production of the present invention, is useful as a chemically useful agent for the prophylaxis and / or treatment of peptic ulcer (eg gastric ulcer , duodenal ulcer, anastomotic ulcer, ulcer caused by nonsteroidal anti-inflammatory agents, ulcer due to postoperative stress); Zollinger-Ellison smdrome; gastritis; erosive esophagitis; symptomatic gastroesophageal reflux disease (symptomatic GERD); Barrett's esophagus, functional dyspepsia; gastric cancer; stomach MALT lymphoma; gastric hyperacidity; or an upper gastrointestinal bleeding inhibitor due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress or ulcer recurrence due to nonsteroidal anti-inflammatory agents. Since the compound (VIII), or a salt thereof, shows low toxicity and is superior in terms of water solubility, in vivo kinetics and expression of efficacy, it is useful as a pharmaceutical composition. Furthermore, since the compound (VIII), or a salt thereof, is stable even under additive conditions, it can be administered orally as a conventional tablet without being formulated as an enteric coated preparation. This has as a consequence that the preparation of the tablet may be smaller, which is advantageous because it can be easily swallowed by patients who have difficulty swallowing, in particular the elderly and children. Additionally, since it lacks the sustained release effect provided by enteric coated preparations, the expression of a suppressive action of gastric acid secretion is rapid, and the relief of symptoms such as pain is rapid.

Detailed description of the invention

The definition of each symbol in the formula is explained in detail in the following.

Examples of the "hydrocarbon group" of the "optionally substituted hydrocarbon group" for R 1 include a chain or dical hydrocarbon group (eg, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl). Of these, a chain or cyclic hydrocarbon group having a carbon number of 1 to 16 is preferred.

Examples of "alkyl" include C1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl).

Examples of "alkenyl" include C2-6 alkenyl (eg, vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 335 butenyl, 2-methyl-2-propenyl, 1-methyl-2-propenyl, 2- methyl-1-propenyl).

Examples of "alkynyl" include C2-6 alkynyl (eg, ethynyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- hexinyl).

Examples of "cycloalkyl" include C3.7 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl).

Examples of "aryl" include C6-14 aryl (for example, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenyl, 3-biphenyl, 4-biphenyl,

2-antrilo).

Examples of "aralkyl" include C7-16 aralkyl (for example, phenyl-C16 alkyl such as benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylmethyl, 3-phenylpropyl, 4-phenylbutyl, 5 -phenylpentyl, naphthyl-C16 alkyl, diphenyl-C1-4 alkyl).

When the hydrocarbon group mentioned above is alkyl, alkenyl or alkynyl, it is optionally substituted with 1 to 3 substituents selected from (1) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), (2) nitro, (3) cyano, (4) hydroxy, (5) C1-6 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec -butyloxy, pentyloxy, hexyloxy, fluoromethoxy) which optionally has 1 3 halogen atoms (for example, a fluorine atom, a chlorine atom, a bromine atom, 50 an iodine atom), (6) C6 aryloxy 14 (for example, phenyloxy, naphthyloxy), (7) C7-16 aralkyloxy (for example, benzyloxy, phenethyloxy, diphenylmethyloxy, 1-naphthylmethyloxy, 2-naphthylmethyloxy, 2,2-diphenylethyloxy, 3-phenylpropyloxy, 4-phenylbutyloxy, 5 - phenylpentyloxy), (8) mercapto, (9) C1-6 alkylthio (for example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobut ilium, pentylthio, hexylthio) optionally having 1 to 3 halogen atoms (for example, fluorine atom, chlorine atom, bromine atom, iodine atom), (10) C6-14 arylthio (for example, phenylthio, Naphthylthio), (11) C7-16 aralkylthio (for example, benzylthio, phenethylthio, diphenylmethylthio, 1-naphthylmethylthio, 2-naphthylmethylthio, 2,2-diphenylethylthio, 3-phenylpropylthio, 4-phenylbutylthio, 5-phenylpentylthio), ) amino, (13) C1-6 alkylamino mono (for example, methylamino, ethylamino), (14) (C6-14 mono-aryl) -amino (for example, phenylamino, 1-naphthylamino, 2-naphthylamino), (15 ) mono (C7-16 aralkyl) -amino (for example, benzylamino), (16) di (C1,6-alkyl) -amino (for example, dimethylamino,

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diethylamino), (17) di (aryl C6-i4) -amino (for example, diphenylamino), (18) di (aralkyl C7-i6) -amino (for example, dibenzylamino), (19) formyl, (20) ( C1,6 alkyl) -carbonyl (for example, acetyl, propionyl), (21) (C6-14 aryl) -carbonyl (for example, benzoyl, 1-naphthoyl, 2-naphthoyl), (22) carboxyl, (23) C1,6-carbonyl alkoxy (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl), (24) (C6-14 aryloxy) -carbonyl (for example, phenoxycarbonyl), (25) carbamoyl, (26) thiocarbamoyl, ( 27) mono (C1,6 alkyl) carbamoyl (for example, methylcarbamoyl, ethylcarbamoyl), (28) di (C1,6 alkyl) carbamoyl (for example, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl), (29) (aryl C6-14) - carbamoyl (for example, phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl), (30) C1,6-alkyl sulfonyl (for example, methylsulfonyl, ethyl sulfonyl), (31) (C6-14 aryl) -sulfonyl (for example, phenylsulfonyl, 1-naphthylsulfonyl, 2- naphthylsulfonyl), (32) C1,6-alkyl sulfinyl (for example, methylsulfinyl, ethylsulfinyl), (33) (C6-14 aryl) -sulfinyl (for example, phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl), (34) formylamino, (35) C1,6-alkylcarbonylamino ( for example, acetylamino), (36) (C6-14 aryl) -carbonylamino (for example, benzoylamino, naphthoylamino), (37) C1,6-carbonylamino alkoxy (for example, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino), (38 ) C16 alkyl-sulfonylamino (for example, methylsulfonylamino, ethylsulfonylamino), (39) (aryl C6-14) -sulfonylamino (for example, phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino), (40) C1,6-carbonyloxy alkyl ( for example, acetoxy, propionyloxy), (41) (C6-14 aryl) -carbonyloxy (for example, benzoyloxy, naphthylcarbonyloxy), (42) C1,6-carbonyloxy (for example, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (43) mono (C1,6 alkyl) carbamoyloxy (for example, methylcarbamoyloxy, ethylcarbamoyloxy), (44) di (C1,6 alkyl) carba moyloxy (for example, dimethylcarbamoyloxy, diethylcarbamoyloxy), (45) (C6-14 aryl) -carbamoyloxy (for example, phenylcarbamoyloxy, naphthylcarbamoyloxy), (46) a saturated 5- to 7-membered dichloric amino (for example, pyrrolidine-1 - ilo, piperidino, piperazine-1-yl, morpholino, thiomorpholino, hexahydroazepine-1-yl) optionally containing, in addition to a nitrogen atom and a carbon atom, 1 0 2 classes of 1 to 4 heteroatoms chosen from a nitrogen atom, a sulfur atom and an oxygen atom, (47) a 5-10 membered aromatic heterodyl group (for example, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4- isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2- benzothiazolyl, 2-benzo [b] thienyl, 3-benzo [b] thienyl, 2- benzo [b] furanyl, 3-benzo [b] furanyl) containing, in addition to a carbon atom, 1 or 2 kinds of 1 to 4 heteroatoms chosen ap Artir of a nitrogen atom, a sulfur atom and an oxygen atom, (48) C1-3-dioxy alkylene (for example, methylenedioxy, ethylenedioxy), (49) C3.7 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl).

Additionally, when the hydrocarbon group mentioned above is cycloalkyl, aryl or aralkyl, it is optionally substituted with 1 to 5 (preferably 1 to 3) substituents selected from (1) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), (2) nitro, (3) cyano, (4) hydroxy, (5) C16 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, fluoromethoxy) optionally having 1 to 3 halogen atoms (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), (6) C6-14 aryloxy (for example, phenyloxy, naphthyloxy), (7) C7-16 aralkyloxy (for example, benzyloxy, phenyloxy, diphenylmethyloxy, 1-naphthylmethyloxy, 2-naphthylmethyloxy, 2,2-diphenylethyloxy, 3- phenylpropyloxy, 4- phenylbutyloxy, 5-phenylpentyloxy), (8) mercapto, (9) C16 alkylthio (for example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio) optionally having 1 to 3 halogen atoms (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), ( 10) C6-14 arylthio (for example, phenylthio, naphthylthio), (11) C7-16 aralkylthio (for example, benzylthio, phenylthio, diphenylmethylthio, 1-naphthylmethylthio, 2-naphthylmethylthio, 2,2-diphenylethylthio, 3-phenylpropylthio, 4-phenylbutylthio, 5-phenylpentylthio), (12) amino, (13) monoalkylamino (e.g., methylamino, ethylamino), (14) mono (C6-14 aryl) -amino (e.g., phenylamino, 1-naphthylamino, 2 -naphthylamino), (15) mono (C7-16 aralkyl) -amino (for example, benzylamino), (16) di (C1,6 alkyl) amino (for example, dimethylamino, diethylamino), (17) di (C6 aryl -14) -amino (for example, diphenylamino), (18) di (C7-16 aralkyl) -amino (for example, dibenzylamino), (19) formyl, (20) C1,6-alkylcarbonyl (for example, acetyl , propionyl), (21) (C6-14 aryl) -carbonyl (for example, benzoyl, 1-naphthoyl, 2-naphthoyl), (22) carboxyl, (23) C16 alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl), (24) (C6-14 aryloxy) -carbonyl (for example, phenoxycarbonyl), (25) carbamoyl, (26) thiocarbamoyl, (27) mono (C1,6 alkyl) carbamoyl (for example, methylcarbamoyl, ethylcarbamoyl), (28) di (C1,6 alkyl) carbamoyl (for example, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl), (29) (C6 aryl -14) -carbamoyl (for example, phenylcarbamoyl, 1-naphthylcarbamoyl, 2- naphthylcarbamoyl), (30) C1,6-alkyl sulfonyl (for example, methylsulfonyl, ethylsulfonyl, trifluoromethylsulfonyl) optionally having 1 to 3 halogen atoms ( for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), (31) (C6-14 aryl) -sulfonyl (for example, phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl), (32) C1,6-alkyl sulfinyl (for example, methylsulfinyl, ethylsulfinyl), (33) (C6-14 aryl) -sulfinyl (for example, phenylsulfinyl, 1- naphthylsulfinyl, 2-naphthylsulfinyl), (34) formylamino, (35) C1-6 alkylcarbonylamino (for example, acetylamino), (36) (aryl C6-14) -carbonylamino (for example, benzoylamino, naphthoylamino), (37) alkoxy C1,6-carbonylamino (for example, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino), (38) alkyl C1,6-sulfonylamino (for example, methylsulfonylamino, ethylsulfonylamino), (39) (aryl C6-14) -sulfonylamino (for example , phenylsulfonylamino, 2- naphthylsulfonylamino, 1-naphthylsulfonylamino), (40) C1,6 alkylcarbonyloxy (for example, acetoxy, propionyloxy), 41) (aryl C6-14) -carbonyloxy (for example, benzoyloxy, naphthylcarbonyloxy), ( 42) C1,6 alkoxycarbonyloxy (for example, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (43) mono (C1,6 alkyl) carbamoyloxy (for example,

methylcarbamoyloxy, ethylcarbamoyloxy), (44) di-C1,6-carbamoyloxy alkyl (eg, dimethylcarbamoyloxy,

diethylcarbamoyloxy), (45) (C6-14 aryl) -carbamoyloxy (for example, phenylcarbamoyloxy, naphthylcarbamoyloxy), (46) a saturated 5- to 7-membered dichloric amino (for example, pyrrolidine-1-yl, piperidine, piperazine-1 -ilo, morpholino, thiomorpholino, hexahydroazepine-1-yl) which optionally contains, in addition to a nitrogen atom and a carbon atom, 1 or 2 classes of 1 to 4 heteroatoms selected from a nitrogen atom, an atom of sulfur and a atom of

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oxygen, (47) a 5- to 10-membered aromatic heterodclic group (eg, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4- isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo [b] thienyl, 3- benzo [b] thienyl, 2- benzo [b] furanyl, 3-benzo [b] furanyl) containing, in addition to a carbon atom, 1 or 2 classes of 1 to 4 heteroatoms chosen from a nitrogen atom, a sulfur atom and an oxygen atom, (48) Ci-3-dioxy alkylene (for example, methylenedioxy, ethylenedioxy), (49) C3.7 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), (50) a Ci, 6-alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl) optionally having 1 to 3 halogen atoms (for example , fluorine, chlorine, bromine, iodine), (51) a C2-6 alkenyl group (for example, allyl, isopropenyl, isobutenyl, 1-methylanyl, 2-pentenyl, 2-hexenyl) optionally having 1 to 3 atoms of halogen (for example, fluorine, chlorine, bromine, iodine), (52) a C2-6 alkynyl group (for example, propargyl, 2- butynyl, 3-butynyl, 3-pentinyl, 3-hexinyl), (53) mono -C3-7cycloalkylcarbamoyl (for example,

cyclopropylcarbamoyl, cyclobutylcarbamoyl), and (54) 5-10 membered heterocyclyl carbonyl containing, in addition to a carbon atom, 1 or 2 classes of 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (for example, 4-morpholinocarbonyl).

Examples of "heterodclic group" of the "optionally substituted heterodyl group" for R1 include a 3- to 8-membered heterocyclic group (preferably, a 5- or 6-membered heterodyl group) containing 1 to 4 heteroatoms such as a nitrogen atom (optionally oxidized), an oxygen atom, a sulfur atom (optionally mono- or di-oxidized), or a 3- to 8-membered heterodyl group (preferably a 5 or 6-membered heterodyl group) containing 1 to 4 heteroatoms such as a nitrogen atom (optionally oxidized), an oxygen atom, a sulfur atom (optionally mono- or di-oxidized), with a benzene ring; or a group formed by condensation of a heterocyclic group of 3 to 8 members (preferably a heterodclic group of 5 or 6 members) containing 1 to 4 heteroatoms such as a nitrogen atom (optionally oxidized), an oxygen atom, a sulfur atom (optionally mono- or di-oxidized), preferably a group formed by condensation of the 5- or 6-membered heterodyl group with a 5 or 6-membered ring containing 1 to 4 heteroatoms such as a nitrogen atom ( optionally oxidized), an oxygen atom, a sulfur atom (optionally mono- or di-oxidized).

Specifically, aziridinyl (for example, 1- or 2-aziridinyl), azirinyl (for example, 1- or 2-azirinyl), acetyl (for example, 2-, 3- or 4-acetyl), azetidinyl (for example, are used , 1-, 2- or 3- azetidinyl), perhydroazepinyl (for example, 1-, 2-,

3- or 4-perhydroazepinyl), perhydroazocinyl (for example, 1-, 2-, 3-, 4- or 5-perhydroazocinyl), pyrrolyl (for example, 1-,

2- or 3-pyrrolyl), pyrazolyl (for example, 1-, 3-, 4- or 5- pyrazolyl), imidazolyl (for example, 1-, 2-, 4- or 5-imidazolyl), triazolyl (for example , 1,2,3-triazol-1-, 4- or 5-yl, 1,2,4, triazol-1 -, 3-, 4- or 5- yl), tetrazolyl (for example, tetrazol-1- , 2- or 5-yl), furyl (for example, 2- or 3-furyl), thienyl (for example, 2- or 3-thienyl), thienyl wherein the sulfur atom is oxidized (for example, 2- or 3-thienyl-1,1-dioxide), oxazolyl (for example, 2-, 4- or 5-oxazolyl), isoxazolyl (for example,

3-, 4- or 5-isoxazolyl), oxadiazolyl (for example, 1,2,3-oxadiazol-4- or 5-yl, 1,2,4-oxadiazol-3- or 5-yl, 1,2, 5- oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl), thiazolyl (for example, 2-, 4- or 5-thiazolyl), isothiazolyl (for example, 3-, 4- or 5- isothiazolyl), thiadiazolyl (for example, 1,2,3-thiadiazol-4- or 5-yl, 1,2,4-thiadiazol-3- or 5-yl, 1,2,5-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl), pyrrolidinyl (for example, 1-, 2- or 3-pyrrolidinyl), pyridyl (for example, 2-, 3- or 4-pyridyl), pyridyl wherein an atom of nitrogen is oxidized (for example, 2-, 3- or 4-pyridyl-N-oxido), pyridazinyl (for example, 3- or 4- pyridazinyl), pyridazinyl where one or both nitrogen atoms are oxidized (for example, 3-, 4-, 5- or 6- pyridazinyl-N-oxide), pyrimidinyl (for example, 2-, 4- or 5-pyrimidinyl), pyrimidinyl wherein one or both nitrogen atoms is (n ) oxidized (for example, 2-, 4-, 5- or 6-pyrimidinyl-N-oxide), pyrazinyl, piperidinyl (for example, 1-, 2-, 3- or 4-piperidinyl o), piperazinyl (for example, 1- or 2-piperazinyl), indolyl (for example, 3H-indole-2-, 3-, 4-, 5-, 6- or 7- yl), pyranyl (for example, 2-, 3- or 4-pyranyl), thiopyranyl (for example, 2-, 3- or 4-thiopyranyl), thiopyranyl where the sulfur atom is oxidized (for example, 2-, 3- or 4-thiopyranyl- 1,1-dioxide), morpholinyl (for example, 2-, 3- or 4- morpholinyl), thiomorpholinyl, quinolyl (for example, 2-, 3-, 4-, 5-, 6-, 7- or 8- quinolyl), isoquinolyl, pyrido [2,3-d] pyrimidinyl (for example, pyrido [2,3-d] pyrimidin-2-yl), naphthyridinyl such as 1,5-, 1,6-, 1,7- , 1,8-, 2,6-or 2,7-naphthyridinyl (for example, 1,5-naphthyridin-2- or 3-yl), thieno [2,3-d] pyridyl (for example, thieno [2 , 3-d] pyridin-3-yl), pyrazinoquinolyl (for example, pyrazino [2,3-d] quinolin-2-yl), chromenyl (for example, 2H-chromen-2- or 3-yl), 2 -benzo [b] thienyl, 3-benzo [b] thienyl, 2- benzo [b] furanyl, 3-benzo [b] furanyl, 2,3-dihydro-1-benzofuranyl, 2,1,3-benzothiadiazolyl, 2 , 3-dihydro-1,4-benzodioxy-5-o -6-yl, 1,3-benzo thiazol-6-yl, 1,1-dioxide-2,3-dihydro-1-benzothien-6-yl, 1-benzothienyl.

Examples of "substituents" of the heterocyclic group include those similar to the substituents optionally present when the "hydrocarbon group" for R1 mentioned above is cycloalkyl, aryl or aralkyl. The number of substituents is 1 to 5, preferably 1 to 3.

Examples of "alkyl group" of "optionally substituted alkyl group" for R2 include C16 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl.

As a substituent optionally possessing the "alkyl group", there can be mentioned (1) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), (2) nitro , (3) cyano, (4) hydroxy, (5) C16 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, fluoromethoxy) optionally having 1 to 3 atoms halogen (for example, fluorine, chlorine, bromine, iodine), (6) C6-14 aryloxy (for example, phenyloxy, naphthyloxy), (7) C7-16 aralkyloxy (for example, benzyloxy, phenyloxy, diphenylmethyloxy, 1- naphthylmethyloxy, 2-naphthylmethyloxy, 2,2-diphenylethyloxy, 3-phenylpropyloxy, 4-phenylbutyloxy, 5-phenylpentyloxy), (8) mercapto, (9)

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C 1 alkylthio (6, for example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio), which optionally has 1 to 3 halogen atoms (for example, fluorine , chlorine, bromine, iodine), (10) C6-14 arylthio (for example, phenylthio, naphthylthio), (11) C7-16 aralkylthio (for example, benzylthio, phenylthio, diphenylmethylthio, 1-naphthylmethylthio, 2-naphthylmethylthio, 2 , 2-diphenylethylthio, 3-phenylpropylthio, 4-phenylbutylthio, 5-phenylpentylthio) (12) amino, (13) mono (C1,6 alkyl) amino (e.g., methylamino, ethylamino), (14) mono (C6- aryl) 14) -amino (for example, phenylamino, 1-naphthylamino, 2-naphthylamino), (15) mono (C7-16 aralkyl) -amino (for example, benzylamino), (16) di (C1.6 alkyl) amino ( for example, dimethylamino, diethylamino), (17) di (C6-14 aryl) -amino (for example, diphenylamino), (18) di (aralkyl C7-16) -amino (for example, dibenzylamino), (19) formyl , (20) C1,6-alkylcarbonyl (for example, acetyl, propionyl), (21) (C6-aryl) 14) -carbonyl (for example, benzoyl, 1-naphthoyl, 2-naphthoyl), (22) carboxyl, (23) C16 alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl), (24) ( C6-14 aryloxy) - carbonyl (for example, phenoxycarbonyl), (25) carbamoyl, (26) thiocarbamoyl, (27) mono (C ^ a-carbamoyl alkyl (for example, methylcarbamoyl, ethylcarbamoyl), (28) di (alkyl C1.6) carbamoyl (for example, dimethylcarbamoyl,

diethylcarbamoyl, ethylmethylcarbamoyl), (29) (aryl C-6-14) carbamoyl (for example, phenylcarbamoyl, 1-naphthylcarbamoyl, 2- naphthylcarbamoyl), (30) alkyl C1,6-sulfonyl (for example, methylsulfonyl, ethyl sulfonyl), (31) (C6-14 aryl) -sulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl), (32) C1,6-alkyl sulfinyl (e.g., methylsulfinyl, ethylsulfinyl), (33) (C6 aryl -14) -sulfinyl (for example, phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl), (34) formylamino, (35) C1,6 alkylcarbonylamino (for example, acetylamino), (36) (C6-14 aryl) -carbonylamino (for example, benzoylamino, naphthoylamino), (37) C1,6-carbonylamino alkoxy (for example, methoxycarbonylamino, ethoxycarbonylamino,

propoxycarbonylamino, butoxycarbonylamino), (38) C1,6-sulfonylamino alkyl (eg, methylsulfonylamino,

ethylsulfonylamino), (39) (C6-14 aryl) -sulfonylamino (for example, phenylsulfonylamino, 2-naphthylsulfonylamino, 1- naphthylsulfonylamino), (40) C1,6-alkylcarbonyloxy (for example, acetoxy, propionyloxy), (41) (C6-14 aryl) -carbonyloxy (for example, benzoyloxy, naphthylcarbonyloxy), (42) C1,6-carbonyloxy alkoxy (for example, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (43) mono (C1,6 alkyl) carbamoyloxy (for example, methylcarbamoyloxy,

ethylcarbamoyloxy), (44) di (C1,6 alkyl) carbamoyloxy (for example, dimethylcarbamoyloxy, diethylcarbamoyloxy), (45) (C6-14 aryl) -carbamoyloxy (for example, phenylcarbamoyloxy, naphthylcarbamoyloxy), (46) a saturated cyclic amino of 5 to 7 members which optionally contain, in addition to a nitrogen atom and a carbon atom, 1 or 2 classes of 1 to 4 heteroatoms chosen from a nitrogen atom, a sulfur atom and an oxygen atom (for example , pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-1-yl), (47) a 5- to 10-membered aromatic heterocyclic group that contains, in addition to a carbon atom, 1 or 2 classes of 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (for example, 2-thienyl,

3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3- isoquinolyl, 4-isoquinolyl, 5- isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo [b] thienyl, 3- benzo [b] thienyl, 2-benzo [b] furanyl, 3-benzo [b] furanyl, (48) C1-3-dioxy alkylene (for example, methylenedioxy, ethylenedioxy), and (49) C3.7 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl).

The number of substituents is 1 to 3.

As "acyl group" for R2, there can be mentioned an acyl group having 1 to 20 carbon atoms, which is derived from organic carboxylic acid. For example, C1-7 alkanoyl groups (for example, formyl; C1,6 alkylcarbonyl such as acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl), (C6-14 aryl) -carbonyl groups can be used for example, benzoyl naphthalenecarbonyl), C1,6-carbonyl alkoxy groups (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl), groups (C6-14-aryloxycarbonyl) for example, a phenoxycarbonyl group), (C7-19 aralkyl) -carbonyl groups (for example, C1-4-phenylalkylcarbonyl such as benzylcarbonyl, phenylcarbonyl, phenylpropylcarbonyl, benzhydrylcarbonyl, naphthyl (C1-4alkyl) carbonyl such as naphthylethylcarbonyl), groups (C7-19 aralkyl) -oxycarbonyl (for example, phenyl (C1-4alkyl) oxycarbonyl such as benzyloxycarbonyl), a 5- or 6-membered heterocyclylcarbonyl group or condensed heterocyclyl-carbonyl groups thereof (for example, a heter group 5 or 6-membered oxycyl carbonyl containing 1 to 4 heteroatoms such as a nitrogen atom (optionally oxidized), an oxygen atom, a sulfur atom (optionally mono or dioxidized), for example pyrrolylcarbonyl such as 2- or 3 - pyrrolylcarbonyl; pyrazolylcarbonyl such as 3-, 4- or 5-pyrazolylcarbonyl; imidazolylcarbonyl such as 2-, 4- or 5- imidazolylcarbonyl; triazolylcarbonyl such as 1,2,3-triazol-4-ylcarbonyl, 1,2,4-triazol-3-ylcarbonyl; tetrazolylcarbonyl such as 1H- or 2H-tetrazol-5-ylcarbonyl; furylcarbonyl such as 2- or 3-furylcarbonyl; thienylcarbonyl such as 2- or 3-thienylcarbonyl; oxazolylcarbonyl such as 2-, 4- or 5-oxazolylcarbonyl; isoxazolylcarbonyl such as 3-,

4- or 5- isoxazolylcarbonyl; oxadiazolylcarbonyl such as 1,2,3-oxadiazol-4- or 5-ylcarbonyl, 1,2,4-oxadiazol-3- or 5- ylcarbonyl, 1,2,5-oxadiazol-3- or 4-ylcarbonyl, 1, 3,4-oxadiazol-2-ylcarbonyl; thiazolylcarbonyl such as 2-, 4- or 5- thiazolylcarbonyl; isothiazolylcarbonyl such as 3-, 4- or 5-isothiazolylcarbonyl; thiadiazolylcarbonyl such as 1,2,3-thiadiazol-

4- or 5-ylcarbonyl, 1,2,4-thiadiazol-3- or 5-ylcarbonyl, 1,2,5-thiadiazol-3- or 4-ylcarbonyl, 1,3,4-thiadiazol-2-ylcarbonyl; pyrrolidinylcarbonyl such as 2- or 3-pyrrolidinylcarbonyl; pyridylcarbonyl such as 2-, 3- or 4-pyridylcarbonyl; pyridylcarbonyl wherein the nitrogen atom is oxidized such as 2-, 3- or 4-pyridyl-N-oxidocarbonyl; pyridazinylcarbonyl such as 3- or 4-pyridazinylcarbonyl; pyridazinylcarbonyl wherein one or both nitrogen atoms are oxidized, such as 3-, 4-, 5- or 6-pyridazinyl-N-oxidocarbonyl; pyrimidinylcarbonyl such as 2-, 4- or 5- pyrimidinylcarbonyl; pyrimidinylcarbonyl wherein one or both nitrogen atoms are oxidized, such as 2-, 4-,

5- or 6-pyrimidinyl-N-oxidocarbonyl; pyrazinylcarbonyl; piperidinylcarbonyl such as 2-, 3- or 4-piperidinylcarbonyl; piperazinylcarbonyl; indolylcarbonyl such as 3H-indole-2- or 3-ylcarbonyl; pyranylcarbonyl such as 2-, 3- or 4- pyranylcarbonyl; thiopyranylcarbonyl such as 2-, 3- or 4-thiopyranylcarbonyl; quinolylcarbonyl such as 3-, 4-, 5-, 6-, 7- or 8-quinolylcarbonyl; isoquinolylcarbonyl; pyrido [2,3-d] pyrimidinylcarbonyl (for example, pyrido [2,3-d] pyrimidin-2-

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ilocarbonyl); naphthyridinylcarbonyl such as 1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridinylcarbonyl (for example 1,5-naphthyridine-2- or 3-ylcarbonyl) ; thieno [2,3-d] pyridylcarbonyl (for example, thieno [2,3-d] pyridin-3-ylcarbonyl); pyrazinoquinolylcarbonyl (for example, pyrazino [2,3-b] quinolin-2-ylcarbonyl); Chromenylcarbonyl (for example, 2H-chromen-2- or 3-ylcarbonyl), a 5- or 6-membered heterocyclyl-acetyl group (for example, a 5- or 6-membered heterocyclyl-acetyl group containing 1 to 4 heteroatoms such as a nitrogen atom (optionally oxidized), an oxygen atom, a sulfur atom (optionally mono or dioxidized), such as 2-pyrrolylacetyl, 3- imidazolylacetyl, 5-isoxazolylacetyl.

With regard to the substituent of the acyl group, for example, when the acyl group mentioned above is an alkanoyl group or an alkoxycarbonyl group, the acyl group is optionally substituted with 1 to 3 alkylthio groups (for example, C1-4 alkylthio such as methylthio, ethylthio, n-propylthio, isopropylthio), halogen (for example, fluorine, chlorine, bromine, iodine), alkoxy groups (for example, C1,6alkoxy such as methoxy, ethoxy, n-propoxy, tert-butoxy, n- hexyloxy), nitro groups, alkoxycarbonyl groups (for example, C1,6 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl), alkylamino groups (by example, mono- or di (C1,6-alkyl alkyl such as methylamino, ethylamino, n-propylamino, n-butylamino, tert-butylamino, n-pentylamino, n-hexylamino, dimethylamino, diethylamino, methylethylamino, di- (n-propyl ) amino, di- (n-butyl) amino), alkoxyimino groups (eg, alkoxy Mino such as methoxyimino, ethoxyimino, n-propoxyimino, tert-butoxyimino, n-hexyloxy-imino) or hydroxyimino.

When the acyl group mentioned above is an arylcarbonyl group, an aryloxycarbonyl group, an aralkylcarbonyl group, an aralkyloxycarbonyl group, a 5- or 6-membered heterocyclyl-carbonyl group or a 5 or 6-heterocyclyl-acetyl group 6 members, is optionally substituted with 1 to 5 (preferably 1 to 3) alkyl groups (for example, C16 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, C3-6 cycloalkyl such as cyclohexyl), alkenyl groups (eg, C2-6 alkenyl such as allyl, isopropenyl, isobutenyl, 1-methyllayl, 2 -pentenyl, 2-hexenyl), alkynyl groups (for example, C2-6 alkynyl such as propargyl, 2-butynyl, 3-butynyl, 3-pentinyl, 3-hexinyl, alkoxy groups (for example, C1,6alkoxy as methoxy , ethoxy, n-propoxy, tert-butoxy, n-hexyloxy), acyl groups (for example, C1-7 alkanoyl such as formyl, acetyl, propionyl , butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl; (C6-14 aryl) -carbonyl such as benzoyl, naphthalenecarbonyl; C1,6-carbonyl alkoxy such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl; (C6-14 aryloxy) -carbonyl such as phenoxycarbonyl; (C7-1g aralkyl) -carbonyl such as phenylC 1-4 alkylcarbonyl (for example, benzylcarbonyl, phenethylcarbonyl, phenylpropylcarbonyl; (C7-1g aralkyl) -oxycarbonyl such as phenylC 1-4 alkyloxycarbonyl (for example, benzyloxycarbonyl) , nitro, amino, hydroxy, cyano, sulfamoyl, mercapto, halogen (for example, fluorine, chlorine, bromine, iodine), or alkylthio groups (C-alkylthio such as comomethylthio, ethylthio, n-propylthio, isobutylthio).

Examples of "optionally substituted hydroxy group" for R2 include hydroxy; C16 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, trifluoromethoxy) optionally having 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, iodine) , C6-14 aryloxy (for example, phenyloxy, naphthyloxy), C7-16 aralkyloxy (for example, benzyloxy, phenethyloxy, diphenylmethyloxy, 1-naphthylmethyloxy, 2-naphthylmethyloxy, 2,2-diphenylethyloxy, 3- phenylpropyloxy, 4-phenylbutyloxy, 5-phenylpentyloxy), C1,6-carbonyloxy alkyl (for example, acetoxy, propionyloxy), (C6-14 aryl) -carbonyloxy (for example, benzoyloxy, naphthylcarbonyloxy), C1,6-carbonyloxy alkoxy (for example, methoxycarbonyloxy, ethoxycarbonyloxy , propoxycarbonyloxy, butoxycarbonyloxy), mono (C1,6 alkyl) carbamoyloxy (for example, methylcarbamoyloxy, ethylcarbamoyloxy), di (C1,6alkyl) carbamoyloxy (for example, dimethylcarbamoyloxy, diethylcarbamoyloxy), (C6-14 aryl) - carbamoyloxy (for example , phenylcarbamoyloxy, naphthylcarbamoyloxy).

Examples of "optionally substituted amino group" for R2 include amino; mono (C1-alkyl, e-amino (eg, methylamino, ethylamino); mono (C6-14 aryl) -amino (for example, phenylamino, 1-naphthylamino, 2-naphthylamino); mono (C7-16 aralkyl) -amino (for example, benzylamino); di (C1,6-alkyl-amino (eg, dimethylamino, diethylamino); di (C6-14 aryl) -amino (e.g., diphenylamino); di (C7-16-aralkyl) -amino (by example, dibenzylamino); formylamino; C1,6 alkylcarbonylamino (for example, acetylamino); (C6-14 aryl) -carbonylamino (for example, benzoylamino, naphthoylamino); C1,6-carbonylamino alkoxy (for example, methoxycarbonylamino, ethoxycarbonylamino ,

propoxycarbonylamino, tert-butoxycarbonylamino); (C7-16 aralkyl) -oxycarbonylamino (for example,

benzyloxycarbonylamino); C1-alkyl, e-sulfonylamino (for example, methylsulfonylamino, ethylsulfonylamino); (C6-14 aryl) - sulfonylamino (for example, phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino).

Examples of "optionally substituted hydrocarbon group" for R3 include groups similar to "optionally substituted hydrocarbon group" for R1 mentioned above.

Examples of "optionally substituted heterodyl group" for R3 include groups similar to "optionally substituted heterodyl group" for R1 mentioned above.

Examples of "labile group" for X include halogen atoms such as chlorine, bromine, a hydroxy group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, a p-nitrobenzenesulfonyloxy group, a group or -nitrobenzenesulfonyloxy.

Examples of "alkyl group" for R 4 include C 1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl butyl, isobutyl, sec-butyl, tert-butyl.

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As R3, a "nitrogen-containing monodyl heterodyl group" optionally fused to a benzene ring or a heterocycle is preferred (as heterodyl group, groups similar to the heterodyl group of the "optionally substituted heterodyl group" for R1 mentioned above may be mentioned ( for example, 5 or 6-membered aromatic nitrogen-containing heterodyl groups containing thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl) optionally substituted by 1 to 3 substituents selected from (i) halogen (for example, fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv) Ci alkyl, 6 (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl) optionally substituted with 1 to 5 (preferably 1 to 3) halogens for example, fluorine, chlorine, bromine, iodine), (v) Ci alkoxy, 6 (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy isobuto xi, sec-butoxy, pentyloxy, hexyloxy) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine, chlorine, bromine, iodine), (vi) amino group optionally substituted with Ci alkyl, 6 ( for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl), (vii) oxo, and (viii) Ci, 6-carbonyl alkoxy (for example, methoxycarbonyl, ethoxycarbonyl , propoxycarbonyl, tert-butoxycarbonyl).

As R3, in particular, an aromatic heterocyclic group containing 6-membered nitrogen (for example, pyridyl groups (for example, 2-, 3- or 4-pyridyl), pyrimidinyl groups (for example, 2-, 4) is especially preferred - or 5- pyrimidinyl), pyridazinyl groups (for example, 3- or 4-pyridazinyl) optionally substituted by 1 to 3 substituents selected from (i) halogen (for example, fluorine, chlorine, bromine, iodine), (ii ) hydroxy, (iii) cyano, (iv) C16 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine, chlorine, bromine, iodine), (v) C16 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine, chlorine, bromine, iodine) and (vi) an amino group optionally substituted with C16 alkyl (for example lo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl), and in particular a pyridyl group optionally substituted with 1 to 3 substituents selected from (i) alkyl C16 (for example, methyl, ethyl, propyl, isopropyl, butiyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine, chlorine , bromine, iodine), and (ii) C16 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine, chlorine, bromine, iodine). As R3, a pyridyl group is particularly preferred.

As R1, [1] a C6-14 aryl group (for example, a phenyl group) optionally substituted with 1 to 5 (preferably 1 to 3) substituents selected from (i) a halogen atom (for example) is preferred , fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) C16 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine, chlorine, bromine, iodine), (iv) C16 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine, chlorine, bromine, iodine), (v) acetyl, (vi) C3.7 cycloalkyl (for example, cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, cycloheptyl), (vii) C1,6-sulfonyl alkyl (for example, methylsulfonyl, ethylsulfonyl), (viii) a C16 alkyl group substituted with 1 to 3 hydroxy (for example, hydroxyme tilo, hydroxyethyl), (ix) C16 alkylthio (for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, pentylthio, hexylthio) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for for example, fluorine, chlorine, bromine, iodine) and (x) C1,6-sulfinyl alkyl (for example, methylsulfinyl, ethylsulfinyl,

[2] a thienyl group optionally substituted with 1 to 3 substituents selected from (i) a halogen atom (for example, fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) C16 alkyl (for example , methyl, ethyl, propyl, isopropyl, butiyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (eg, fluorine, chlorine, bromine, iodine ), (iv) C16 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine , chlorine, bromine, iodine), and (v) acetyl, or

[3] a pyridyl group optionally substituted with 1 to 4 substituents selected from (1) a halogen atom (eg, fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) lower alkyl (3) is preferred. specifically C1-6) (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example , fluorine, chlorine, bromine, iodine), (iv) C16 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy) optionally substituted with 1 to 5 (preferably 1 to 3 ) halogens (for example, fluorine, chlorine, bromine, iodine), (v) acyl (for example, acetyl), (vi) nitro, and (vii) amino.

Of these, as R1, [1] a C6-14 aryl group (eg, a phenyl group) optionally substituted with 1 to 5 (preferably 1 to 3) substituents selected from (i) a halogen atom is preferred (for example, fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) C16 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl ) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example fluorine, chlorine, bromine, iodine), (iv) C16 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy, pentyloxy, hexyloxy) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine, chlorine, bromine, iodine), and (v) acetyl, 2

[2] a thienyl group optionally substituted with 1 to 3 substituents chosen from (i) a halogen atom (for example, fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) C16 alkyl (for example , methyl, ethyl, propyl, isopropyl, butyl,

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isobutiyl, sec-butyl, tert-butyl, pentyl, hexyl) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine, chlorine, bromine, iodine), (iv) Ci alkoxy, 6 (per example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (eg, fluorine, chlorine, bromine, iodine), and (v) acetyl, or

[3] a pyridyl group optionally substituted with 1 to 4 substituents selected from (i) a halogen atom (for example, fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) lower alkyl (specifically C1 -6) (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine , chlorine, bromine, iodine), (iv) Ci, 6 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine, chlorine, bromine, iodine), (v) acyl (for example, acetyl), (vi) nitro, and (vii) amino.

In particular, [1] a phenyl group optionally substituted with 1 to 5 (preferably 1 to 3) substituents selected from (i) a halogen atom (eg, fluorine, chlorine, bromine, iodine), and (ii) C16 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example , fluorine, chlorine, bromine, iodine),

[2] a thienyl group optionally substituted with 1 to 3 substituents selected from (i) a halogen atom (for example, fluorine, chlorine, bromine, iodine), and (ii) C16 alkyl (for example, methyl, ethyl , propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (eg, fluorine, chlorine, bromine, iodine), or

[3] a pyridyl group optionally substituted with 1 to 4 substituents selected from (i) a halogen atom (for example, fluorine, chlorine, bromine, iodine), and (ii) lower alkyl (specifically C1-6) ( for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine, chlorine, bromine , iodine).

Of those mentioned above, a preferable embodiment of R1 includes [1] a phenyl group optionally substituted with 1 to 5 substituents selected from (i) a halogen atom and (ii) C1,6 alkyl optionally substituted with 1 to 5 atoms halogen, [2] a pyridyl group optionally substituted with 1 to 4 substituents selected from lower (C16) alkyl, a halogen atom, alkoxy (C16 alkoxy), cyano, acyl (eg, acetyl), nitro and amino .

As R1, a phenyl group, a 2-fluorophenyl group, a 2-methylphenyl group, a 2-fluoropyridin-3-yl group, a 3-fluoropyridin-4-yl group, a 2-chloropyridin-3 group are particularly preferred -yl, a 6-chloropyridin-3-yl group, a 4- methylpyridin-3-yl group, a 2-methylpyridin-3-yl group, a 3-methylpyridin-2-yl group, a 2-trifluoromethylpyridin-3 group -yl, and a 6'-chloro-2,3'-bipyridin-5-yl group.

Preferably, it is particularly preferred that R2 is a hydrogen atom, a C16 alkyl group (for example, methyl, ethyl, n-propyl, isobutyl), a Ci, 6-carbonyl alkyl group (for example, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl), a fluorine atom, or a chlorine atom, and a hydrogen atom.

As R4, methyl or ethyl is preferred, and methyl is particularly preferable.

The preferable embodiments mentioned above of the substituents for R1 to R4 may optionally be combined to achieve a preferable embodiment.

In a preferable embodiment, for example, R 3 is a 5 or 6 membered aromatic nitrogen-containing heterodyl group (for example, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl) or an imidazo group [1,2- a] pyrimidinyl, which are optionally substituted by 1 to 3 substituents selected from (i) halogen (eg, fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv) C16 alkyl (for example, methyl, ethyl, propyl, isopropyl, butiyl, isobutiyl, sec-butyl, tert-butyl, pentyl, hexyl) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine, chlorine, bromine, iodine), (v) C16 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for eg, fluorine, chlorine, bromine, iodine), (vi) an amino group optionally substituted with C16 alkyl (for example, methyl, ethyl, propyl, isopropyl, butiyl, isobutiyl, sec-butyl tert-butyl, pentyl, hexyl), and (vii) C-i alkoxy, 6-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl);

R1 is preferably [1] a C16 aryl group (for example, a phenyl group) optionally substituted with 1 to 5 (preferably 1 to 3) substituents selected from (i) a halogen atom (for example, fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) C16 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine, chlorine, bromine, iodine), (iv) C16 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy , hexyloxy) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine, chlorine, bromine, iodine), (v) acetyl, (vi) C3.7 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), (vii) C1,6-sulfonyl alkyl (for example, methylsulfonyl, ethylsulfonyl), (viii) a C16 alkyl group substituted with 1 to 3 hydroxy

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(for example, hydroxymethyl, hydroxyethyl), (ix) C 1 alkylthio (for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, pentylthio, hexylthio) optionally substituted with 1 to 5 (preferably 1 a 3) halogens (for example, fluorine, chlorine, bromine, iodine), and (x) Ci, 6-sulfinyl alkyl (for example, methylsulfinyl, ethylsulfinyl),

[2] a thienyl group optionally substituted with 1 to 3 substituents selected from (i) a halogen atom (eg, fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) Ci alkyl, 6 ( for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine, chlorine, bromine, iodine), (iv) C16 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine , chlorine, bromine, iodine), and (v) acetyl,

[3] a pyridyl group optionally substituted with 1 to 4 substituents selected from (i) a halogen atom (for example, fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) lower alkyl (specifically C1 -6) (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine , chlorine, bromine, iodine), (iv) C16 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine, chlorine, bromine, iodine), (v) acyl (for example, acetyl), (vi) nitro, and (vii) amino, or

[4] a bipyridyl group optionally substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine);

R2 is a hydrogen atom, a C16 alkyl group (for example, methyl, ethyl, n-propyl, isobutyl), a C1,6-carbonyl alkyl group (for example, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl), a fluorine atom or a chlorine atom, and

R4 is methyl or ethyl.

In a particularly preferable embodiment,

R3 is a pyridyl group optionally substituted with 1 to 3 substituents selected from (i) C16 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine, chlorine, bromine, iodine), and (ii) C16 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy , pentyloxy, hexyloxy) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine, chlorine, bromine, iodine),

R1 is [1] a phenyl group optionally substituted with 1 to 5 (preferably 1 to 3) substituents selected from (i) a halogen atom (eg, fluorine, chlorine, bromine, iodine), and (ii) alkyl C16 (for example, methyl, ethyl, propyl, isopropyl, butiyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine, chlorine bromine iodine)

[2] a thienyl group optionally substituted with 1 to 3 substituents selected from (i) a halogen atom (for example, fluorine, chlorine, bromine, iodine), and (ii) C16 alkyl (for example, methyl, ethyl , propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (eg, fluorine, chlorine, bromine, iodine), or

[3] a pyridyl group optionally substituted with 1 to 4 substituents selected from (i) a halogen atom (for example, fluorine, chlorine, bromine, iodine), and (ii) lower alkyl (specifically C1-6) ( for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl) optionally substituted with 1 to 5 (preferably 1 to 3) halogens (for example, fluorine, chlorine, bromine, I give

R2 is a hydrogen atom, and R4 is methyl.

As the halogen atom for X1, chlorine or bromine is preferred, and chlorine is most preferable.

As a labile group for X, a halogen atom such as chlorine, bromine or the like or a hydroxy group is preferred, and a halogen atom is most preferable.

Preferred examples of compound (VIII), which is an object compound, include: 1- {5- (2-fluorophenyl) -1 - [(6-methylpyridin-3-yl) sulfonyl] -1H-pyrrol-3-yl) } -N-methylmethanamine or a salt thereof, 1- [4-fluoro-5-phenyl-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl] -N-methylmethanamine or a salt thereof, N-methyl-1- [5- (4-methyl-3-thienyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl] methanamine or a salt thereof, 1- [5- ( 2-fluoropyridin-3-yl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl] -N-methylmethanamine or a salt thereof, 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl] -N-methylmethanamine or a salt thereof,

N-methyl-1 - [5- (2-methylphenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl] methanamine or a salt thereof.

The method of production of the present invention is explained in detail in the following.

As salts of the compounds (I) - (VIII) in the reaction, where metal salt, ammonium salt, salts with organic bases, salts with inorganic bases, salts with organic acids, salts with 5 basic amino acids can be mentioned or addicos. Preferable examples of metal salt include alkali metal salts such as sodium salt, potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt; aluminum salt Preferable examples of the organic base salt include a salt with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N'-dibenzylethylenediamine. Preferable examples of salt with inorganic acid include a salt with hydrochloric acid, hydrobromic acid, metric acid, sulfuric acid, phosphoric acid. Preferable examples of salt with organic acid include a salt with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, smoking acid, oxalic acid, tartaric acid, maleic acid, citric acid, sucdnic acid, malic acid, methanesulfonic acid, benzenesulfonic acid , p-toluenesulfonic acid. Preferable examples of salt with basic amino acid include a salt with arginine, lysine, ornithine. Preferable examples of salt with addic amino acid include a salt with aspartic acid, glutamic acid.

While the compounds obtained in the respective stages can be used for the next reaction in the form of a reaction mixture or a crude product, they can also be easily isolated and purified from the reaction mixture by means of a known separation and purification medium. , such as recrystallization, distillation, chromatography.

20 (Method 1)

image33

wherein each symbol is as defined above, and Xi is a halogen atom such as chlorine or bromine (preferably chlorine).

Stage 1

The compound (II) or a salt thereof can be produced by cyclization of the compound (I) or a salt thereof, in the presence of hydrogen halide.

This reaction can be carried out according to the method described in JP-A-6-9554, or a method analogous thereto.

The compound (I) or a salt thereof, can be produced, for example, according to the method described in JP-A-6-9554, or a method analogous thereto.

Stage 2

The compound (III) or a salt thereof, can be produced by subjecting the compound (II) or a salt thereof to dehalogenation.

As dehalogenation, a catalytic hydrogenation method can be mentioned.

The catalytic hydrogenation can be carried out in the presence of a source of hydrogen and a metal catalyst. Examples of a metal catalyst include a palladium catalyst (e.g., palladium and carbon, palladium hydroxide and carbon, palladium oxide, nickel catalyst (e.g., Raney nickel), catalyst).

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platinum (for example, platinum oxide, platinum and carbon), rhodium catalyst (for example, rhodium and carbon), cobalt catalyst (for example, Raney-cobalt). Of these, palladium and carbon, or Raney nickel, is preferred. The amount of metal catalyst to be used is about 0.001 to about 10 mol, preferably about 0.001 to about 5 mol, per 1 mol of compound (II).

Examples of the hydrogen source include hydrogen gas, formic acid, ammonium format, triethylammonium format, sodium phosphinate, hydrazine. When a hydrogen source other than hydrogen gas is used, a compound of a hydrogen source is used in about 1 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of compound (II ).

The dehalogenation is preferably performed in the presence of a base. As a base, there may be mentioned, for example, inorganic bases such as sodium hydride, sodium hydroxide, potassium hydroxide, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, metal bases such as potassium ethoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, aromatic amines such as pyridine, lutidine, tertiary amines such as diisopropylethylamine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-N, N-dimethylamine, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine. Tertiary amines such as diisopropylethylamine are preferred. The amount of base to be used is about 1 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of compound (II).

The dehalogenation is generally performed in a solvent inert to the reaction. Examples of said solvent include alcohols (for example, methanol, ethanol, propanol, butanol), hydrocarbons (for example, benzene, toluene, xylene), halogenated hydrocarbons (for example, dichloromethane, chloroform), ethers (for example, diethyl ether , dioxane, tetrahydrofuran), esters (for example, ethyl acetate), amides (for example, N, N-dimethylformamide, N, N-dimethylacetamide), carboxylic acids (for example, acetic acid), water and mixtures thereof . The amount of solvent to be used is generally from about 1 to about 100 ml, preferably about 1 to about 50 ml, per 1 g of compound (II).

The hydrogen pressure under which the reaction is carried out is generally from about 0 to about 10 atm, preferably about 0 to about 5 atm. The reaction temperature is generally from about -50 ° C to about 100 ° C, preferably from about - 20 ° C to about 50 ° C. The reaction time is generally about 0.5 to about 24 hours, preferably about 0.5 to about 10 hours.

Stage 3

The compound (IV) or a salt thereof can be produced by reduction of the compound (III) or a salt thereof, and the hydrolysis of the reduced product.

As a reduction, a method using metal hydride and a method using catalytic hydrogenation can be mentioned.

Examples of metal hydride include boron reagent (for example, sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium cyanoborohydride), aluminum reagent (eg, diisobutylaluminium hydride, hydride of aluminum, lithium aluminum hydride), borane complex (for example, borane-THF complex, borane dimethyl sulphide, borane-pyridine), catechol borane. The amount of metal hydride to be used is, for example, about 0.2 to about 10 mol, preferably about 0.2 to about 5 mol, per 1 mol of compound (III).

The metal hydride reduction reaction is generally carried out in a solvent inert to the reaction. Examples of said solvent include aromatic hydrocarbons (e.g., toluene, xylene, chlorobenzene), aliphatic hydrocarbons (e.g., heptane, hexane), halogenated hydrocarbons (e.g., chloroform, dichloromethane), ethers (e.g., diethyl ether, tetrahydrofuran , dioxane), and a mixture thereof. The amount of solvent to be used is generally about 1 to about 100 ml, preferably about 1 to about 50 ml, per 1 g of compound (III).

The reaction temperature is generally from about -100 ° C to about 100 ° C, preferably from about -70 ° C to about 50 ° C. The reaction time is generally from about 0.5 hours to about 24 hours, preferably from about 0.5 hours to about 5 hours.

Catalytic hydrogenation can be performed in the presence of a source of hydrogen and a metal catalyst. Examples of a metal catalyst include palladium catalyst (e.g., palladium and carbon, palladium hydroxide and carbon, palladium oxide), nickel catalyst (e.g., Raney nickel), platinum catalyst (e.g., platinum oxide , platinum and carbon), rhodium catalyst (for example, rhodium and carbon). Of these, palladium and carbon, or Raney nickel, is preferred. The amount of metal catalyst to be used is about 0.0001 to about 10 mol, preferably about 0.001 to about 5 mol, per 1 mol of compound (III), or about 0.1 g to about 10 g, preferably about 0.3 ga

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approximately 5 g, per 1 g of compound (III).

Examples of the hydrogen source include hydrogen gas, formic acid, ammonium format, triethylammonium format, sodium phosphinate, hydrazine. When a hydrogen source other than hydrogen gas is used, a compound of a hydrogen source is used in about 1 to about 100 mol, preferably about 1 to about 50 mol, more preferably about 1 to about 10 mol, for example, about 1 to about 5 mol, per 1 mol of compound (III).

The catalytic hydrogenation is generally carried out in a solvent inert to the reaction. Examples of said solvent include alcohols (for example, methanol, ethanol, propanol, butanol), aromatic hydrocarbons (for example, benzene, toluene, xylene, chlorobenzene), halogenated hydrocarbons (for example, dichloromethane, chloroform), ethers (for example , diethyl ether, dioxane, tetrahydrofuran), esters (for example, ethyl acetate), amides (for example, N, N-dimethylformamide, N, N-dimethylacetamide), carboxylic acids (for example, acetic acid), water and a mixture thereof. The amount of solvent to be used is, in general, from about 1 to about 1000 ml, preferably about 1 to about 100 ml, per 1 g of compound (III).

The hydrogen pressure under which the reaction is carried out is, in general, from about 0 to about 10 atm, preferably about 0 to about 5 atm. The reaction temperature is, in general, from about -50 ° C to about 100 ° C, preferably from -20 ° C to about 50 ° C. The reaction time is generally about 1 to about 100 hours, preferably about 1 to about 24 hours, for example, about 1 to about 10 hours.

The hydrolysis can be carried out in the presence of an acid or a base. Examples of the acid include inorganic acid (hydrochloric acid, sulfuric acid, metric acid, phosphoric acid, boric acid), organic carboxylic acid (formic acid, acetic acid, propionic acid), organic sulfonic acid (methanesulfonic acid, benzenesulfonic acid, pencene sulfonic acid -toluenesulfonic acid, trifluoromethanesulfonic acid). The amount of acid to be used is about 0.1 to about 10 mol, preferably about 0.1 to about 5 mol, per 1 mol of compound (III). Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate. The amount of base to be used is about 0.1 to about 10 mol, preferably about 0.1 to about 5 mol, per 1 mol of compound (III).

The hydrolysis is advantageously performed using an inert solvent for the reaction. While said solvent is not particularly limited as long as the reaction progresses, there may be mentioned alcohols (for example, methanol, ethanol, propanol, butanol), aromatic hydrocarbons (for example, benzene, toluene, xylene, chlorobenzene), halogenated hydrocarbons (for example, dichloromethane, chloroform), ethers (for example, diethyl ether, dioxane, tetrahydrofuran), amides (for example, N, N-dimethylformamide, N, N-dimethylacetamide), carboxylic acids (for example, (acetic acid) , water and a mixture thereof The amount of solvent to be used is generally about 1 to about 100 ml, preferably about 1 to about 50 ml, per 1 g of compound (III).

The reaction temperature is generally from about -20 ° C to about 100 ° C, preferably about 0 ° C to about 50 ° C. The reaction time is generally about 1 to about 48 hours, preferably about 1 to about 24 hours.

Stage 4

The compound (VI) or a salt thereof can be produced by subjecting the compound (IV) or a salt thereof to a reaction with compound (V) or a salt thereof.

The amount of compound (V) to be used is preferably about 1 to about 10 mol, more preferably about 1 to about 5 mol, per 1 mol of compound (IV).

This reaction is advantageously carried out using an inert solvent for the reaction. While said solvent is not particularly limited as long as the reaction progresses, there may be mentioned alcohols (for example, methanol, ethanol, propanol, butanol), aromatic hydrocarbons (for example, benzene, toluene, xylene, chlorobenzene), halogenated hydrocarbons ( for example, dichloromethane, chloroform), ethers (for example, diethyl ether, dioxane, tetrahydrofuran), esters (for example, ethyl acetate), amides (for example, N, N-dimethylformamide, N, N-dimethylacetamide), nitriles acids (for example, acetonitrile, propionitrile), water and a mixture thereof. The amount of solvent to be used is generally 1 to 100 ml, preferably 1 to 50 ml, per 1 g of compound (IV).

This embodiment is preferably performed in the presence of a base. Examples of the base include inorganic bases such as sodium hydride, sodium hydroxide, potassium hydroxide, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, metal bases such as potassium ethoxide, tert. - potassium butoxide, sodium methoxide, sodium ethoxide, aromatic amines such as pyridine, lutidine, tertiary amines such as diisopropylethylamine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-N, N-dimethylaminopyridine, N, N, N-dimethylan -methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, and a mixture thereof. The amount of base to use is about 0.01 to about 10

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mol, preferably about 0.1 to about 5 mol, per 1 mol of compound (IV).

The reaction may also be carried out in the co-presence of the crown. As ether crown can be mentioned, for example, 15-crown-5-ether, 18-crown-6-ether. The amount of crown ether to be used is about 1 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of compound (IV).

The reaction time is generally from about 30 minutes to about 24 hours, preferably about 30 minutes to about 8 hours. The reaction temperature is generally from about 0 ° C to about 100 ° C, preferably about 10 ° C to about 50 ° C.

Stage 5

The compound (VIII) or a salt thereof can be produced by reacting compound (VI) or a salt thereof with compound (VII) or a salt thereof, and reducing the imine formed. Alternatively, compound (VIII) or a salt thereof can be produced without isolating the imine formed, by carrying out the reaction of compound (VI) or a salt thereof with compound (VII) or a salt thereof in the presence of an agent. reducer.

This reaction can be performed according to the conventional reaction conditions known as the reductive amination reaction. For example, the reaction can be performed according to the method described in Jikken Kagaku Koza (Courses in Experimental Chemistry), vol. 14-III, pages 1380-1385 (Maruzen Co., Ltd.).

The amount of compound (VII) to be used is preferably about 1 to about 10 mol, more preferably about 1 to about 5 mol, per 1 mol of compound (VI).

This reaction is advantageously carried out using an inert solvent for the reaction. While the solvent is not particularly limited as long as the reaction progresses, there may be mentioned alcohols (for example, methanol, ethanol, propanol, butanol), aromatic hydrocarbons (for example, benzene, toluene, xylene, chlorobenzene), halogenated hydrocarbons ( for example, dichloromethane, chloroform), ethers (for example, diethyl ether, dioxane, tetrahydrofuran), esters (for example, ethyl acetate), amides (for example, N, N-dimethylformamide, N, N-dimethylacetamide), water and a mixture of them. The amount of solvent to be used is generally 1 to 100 ml, preferably 1 to 50 ml, per 1 g of compound (VI).

The reaction time is generally about 0.5 to about 24 hours, preferably about 0.5 to about 10 hours. The reaction temperature is generally from about -50 ° C to about 100 ° C, preferably from about -10 ° C to about 50 ° C.

As the reducing agent, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride can be used. The amount of reducing agent to be used is preferably about 0.2 to about 10 mol, more preferably about 0.2 to about 5 mol, per 1 mol of compound (VI).

The reduction can also be done by catalytic hydrogenation.

Catalytic hydrogenation can be carried out in the presence of a source of hydrogen and a metal catalyst. Examples of the metal catalyst include palladium catalyst (e.g., palladium and carbon, palladium hydroxide and carbon, palladium oxide), nickel catalyst (e.g., Raney nickel), platinum catalyst (e.g., platinum oxide, platinum and carbon), rhodium catalyst (for example, rhodium and carbon), cobalt catalyst (for example, Raney-cobalt). Of these, palladium and carbon, or Raney nickel, is preferred. The amount of metal catalyst to be used is about 0.01 to about 10 mol, preferably about 0.01 to about 5 mol, per 1 mol of compound (VI).

As a source of hydrogen, hydrogen gas, formic acid, ammonium format, triethylammonium format, sodium phosphinate, hydrazine can be mentioned. When a hydrogen source other than hydrogen gas is used, a compound of a hydrogen source is used in an amount of about 1 to about 100 mol, preferably about 1 to about 50 mol, more preferably about 1 at about 10 mol, for example about 1 to about 5 mol, per 1 mol of compound (VI).

The reduction is advantageously carried out using an inert solvent for the reaction. Said solvent is not particularly limited as long as the reaction progresses, and there may be mentioned alcohols (for example, methanol, ethanol, propanol, butanol), hydrocarbons (for example, benzene, toluene, xylene), halogenated hydrocarbons (for example, dichloromethane , chloroform), ethers (for example, diethyl ether, dioxane, tetrahydrofuran), esters (for example, ethyl acetate), amides (for example, N, N-dimethylformamide, N, N-dimethylacetamide), water and a mixture of the same. The amount of solvent to be used is generally 1 to 100 ml, preferably 1 to 50 ml, per 1 g of compound (VI).

The reaction time is generally about 0.5 to about 24 hours, preferably about 0.5 to about 10 hours. The reaction temperature is generally from about -50 ° C to about 100 ° C, preferably from -20 ° C to about 50 ° C.

Examples

The present invention will be explained in detail in what follows with reference to Reference Examples and Examples, which are not to be construed as limiting.

In the Reference Examples and in the Examples that follow, "room temperature" generally means about 10 ° C to about 35 ° C, but is not in particular strictly limited. The liquid mixing ratio shows a volume ratio. Unless otherwise specified, "%" means% by weight. The yield is in% mol / mol. Silica gel column chromatography is performed using silica gel 60 (0.063-0.200 mm) manufactured by MERCK or Fuji Silysia Chemical Ltd. Chromatorex (registered trademark) NH (described as basic silica gel column chromatography). The melting point was measured using the Yanagimoto trace melting point measuring device 10 or the trace melting point measuring device (B-545), and uncorrected. For the 1H-NMR spectrum, tetramethylsilane was used as an internal standard, and Bruker DPX-300 (300 MHz) or Bruker AVANCEIII500 (5OO MHz) was used for measurement.

The abbreviations that follow in the Examples and Reference Examples, mean the following:

s: singlet, d: doublet, dd: double doublet, dt: double triplet, t: triplet, q: quartet, m: multiplet, br: extensive, brs: 15 extensive singlet, J: coupling constant, Hz: Hertz, THF: tetrahydrofuran, HPLC: high performance liquid chromatography.

Reference Example 1

2-Chloro-5- (2-fluorophenyl) -1H-pyrrole-3-carbonitrile

[2- (2-fluorophenyl) -2-oxoethyl] propanedinitrile (135.0 g, 667.7 mmol) and ethyl acetate (540 ml) were added in a four-neck flask, 4 N chlortndric acid-acetate ethyl (417 ml, 1.67 mol), and the mixture was stirred at the internal temperature of 40-50 ° C for 2.5 hours. Ethyl acetate (270 ml) was added, and the mixture was stirred at an internal temperature of 70-80 ° C for 2 hours. The internal temperature was cooled to 50 ° C, and initiator crystals (68 mg) of the above compound were added. The mixture was continuously stirred at the internal temperature of 20-30 ° C for 0.5 hours and at the internal temperature of 0-10 ° C for 1 hour. The precipitated crystals were collected by filtration, washed with fno ethyl acetate (270 ml), and dried under reduced pressure at 50 ° C until a constant weight was reached to provide the title compound (73.9 g, 50.2% yield).

1H-NMR (300 MHz, DMSO-d6) S (ppm): 6.91 (d, J = 2.0 Hz, 1H), 7.27-7.42 (m, 3H), 7.70-7 , 75 (m, 1H), 13.05 (brs, 1H). Elementary analysis (C11H6N2CF)

30 Calculated: C: 59.88, H: 2.74, N: 12.70, Cl: 16.06, F: 8.61.

Found: C: 59.74, H: 2.75, N: 12.75, Cl: 16.02, F: 8.51 melting point 218-220 ° C Reference Example 2 2-Chloro-5- ( 2-fluorophenyl) -1H-pyrrole-3-carbonitrile

[2- (2-Fluorophenyl) -2-oxoethyl] propanedinitrile (5.0 g, 24.7 mmol) and THF (50 ml) were added in a four-mouth flask, and then chlortindric acid gas ( 5 g, 137 mmol). The mixture was stirred at an internal temperature of 55-65 ° C for 3 hours. Acetonitrile (20 ml) was added, and the mixture was concentrated to approximately 17.5 g. Acetonitrile (20 ml) was added and the mixture was concentrated again to approximately 17.5 g. Acetonitrile (17.5 ml) was added, and water (15 ml) was added dropwise at the internal temperature of 55-65 ° C. The mixture was stirred continuously at the internal temperature of 55-65 ° C for 1 hour and at the internal temperature of 20-30 ° C for 1 hour. The precipitated crystals were collected by filtration, washed with a cold mixed solution of acetonitrile and water (1: 1, 10 ml), and dried under reduced pressure at 50 ° C until a constant weight was reached to provide the compound of the stated (4.59 g, yield 84.2%).

1H-NMR (500 MHz, CDCla) S (ppm): 6.77-6.78 (m, 1H), 7.14-7.23 (m, 2H), 7.28-7.31 (m, 1H), 7.51-7.55 (m, 1H), 9.21 (brs, 1H).

Reference Example 3

[2- (2-methylphenyl) -2-oxoethyl] propanedinitrile

2-Methylacetophenone (466 mmol, 62.5 g) and ethyl acetate (375 ml) were added in a four-mouth flask. The internal temperature was maintained at 25 + 5 ° C, and a solution of bromine (489 mmol, 50 78.1 g) in ethyl acetate (180 ml) was slowly added dropwise. Once the dropwise addition was completed, the mixture was stirred thereto.

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temperature for 1 hour. Tap water (375 ml) was added dropwise at the internal temperature of no more than 35 ° C, sodium sulphite (89.4 mmol, 11.3 g) was added, and the mixture was stirred at room temperature for 1 hour. The organic layer was separated, and washed successively with 3% aqueous sodium bicarbonate solution (374 ml) and 10% brine (375 ml) to obtain a solution of 2-bromo-1- (2-methylphenyl) ethanone in ethyl acetate.

The solution of 2-bromo-1- (2-methylphenyl) ethanone in ethyl acetate obtained above was cooled, malononitrile (466 mmol, 30.8 g) was added at the internal temperature of 5 + 5 ° C, and the drip funnel was washed with ethyl acetate (40 ml) and the wash product was added. Diisopropylethylamine (513 mmol, 87.8 ml) was added dropwise at the internal temperature of 10 + 5 ° C. After the dropwise addition, the mixture was stirred at the internal temperature of 5 + 5 ° C for 2 hours. Tap water (375 ml) was added, and the mixture was partitioned at room temperature. The aqueous layer was extracted with ethyl acetate (188 ml). The organic layers were combined and washed with a mixture of 1 N chlortndric acid (18.8 ml) and 10% brine (188 ml), and 10% brine (188 ml) in this order. The organic layer was concentrated in about half of the amount under reduced pressure. Methanol (375 ml) was added to the concentrate, and the mixture was concentrated to approximately 239 g. This operation was performed a total of 3 times. Water (27.7 ml) was added while stirring the concentrate with heating at 55 + 5 ° C and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was gradually cooled to no more than 30 ° C, further cooled to the internal temperature of 5 + 5 ° C, and stirred for 1 hour. The precipitated crystals were collected by filtration, cooled and washed with a mixture of methanol (24 ml) and water (3.6 ml). The humerus crystals were dried under reduced pressure at 50 ° C to obtain the title compound (70.3 g, 76% yield).

melting point 92.0-93.0 ° C.

1H-NMR (300 MHz, DMSO-d6) S (ppm): 2.47 (s, 3H), 4.01 (d, J = 6.04 Hz, 2H), 5.08 (t, J = 6 , 04 Hz, 1H), 7.33-7.40 (m, 2H), 7.48-7.54 (m, 1H), 7.90 (d, J = 7.84 Hz, 1H).

elemental analysis (C12H10N2O)

Calculated: C: 72.71, H: 5.08, N: 14.13, O: 8.07.

Found: C: 72.87, H: 5.06, N: 13.95

Reference Example 4

[2- (2-methylphenyl) -2-oxoethyl] propanedinitrile

2-Methylacetophenone (466 mmol, 62.5 g) and ethyl acetate (375 ml) were added in a four-mouth flask. While maintaining the internal temperature at 25 + 5 ° C, a solution of bromine (489 mmol, 78.1 g) in ethyl acetate (180 ml) was slowly added dropwise. Once the addition was finished drop by drop, the mixture was stirred at the same temperature for 1 hour. Tap water (375 ml) was added dropwise at the internal temperature of no more than 35 ° C, sodium sulphite (89.4 mmol, 11.3 g) was added, and the mixture was stirred at room temperature for 1 hour. The organic layer was separated and washed successively with 3% aqueous sodium bicarbonate solution (375 ml) and 10% brine (375 ml) to obtain a solution of 2-bromo-1- (2-methylphenyl) ethanone in ethyl acetate.

The solution of 2-bromo-1- (2-methylphenyl) ethanone in ethyl acetate obtained above was cooled, malononitrile (466 mmol, 30.8 g) was added at the internal temperature of 5 + 5 ° C, and the funnel drip was washed with ethyl acetate (40 ml) and the wash product was added. Diisopropylethylamine (513 mmol, 87.8 ml) was added dropwise at the internal temperature of 10 + 5 ° C. After the dropwise addition, the mixture was stirred at the internal temperature of 5 + 5 ° C for 2 hours. Tap water (375 ml) was added, and the mixture was partitioned at room temperature. The aqueous layer was further extracted with ethyl acetate (188 ml). The organic layers were combined and washed with a mixture of 1 N chlortndric acid (18.8 ml) and 10% brine (188 ml), and 10% brine (188 ml) in this order. The organic layer was concentrated to about half of the amount under reduced pressure. Methanol (375 ml) was added to the concentrate, and the mixture was concentrated to approximately 388 g. This operation was performed a total of 3 times to obtain a grout of the compound of the sentence and methanol.

Reference Example 5

[2- (2-methylphenyl) -2-oxoethyl) propanedinitrile

2-Methylacetophenone (30 g, 223.5 mmol) and ethyl acetate (180 ml) were mixed, and a mixture of bromine (39 g) and ethyl acetate (90 ml) was added dropwise at room temperature for approximately Three hours. Then, water (180 ml) was added dropwise, and the mixture was stirred at room temperature for about 1 hour. Aqueous sodium sulphite solution (186 ml) was added dropwise to the reaction mixture for about 1 hour, the mixture was partitioned and the organic layer was washed with 3% aqueous sodium bicarbonate solution (186 ml) and 10% aqueous sodium chloride solution (198 ml) to obtain a solution of 2-bromo-1- (2-methylphenyl) ethanone in ethyl acetate.

Malononitrile (14.8 g) was added, and ethyl acetate (20 ml) was added. Diisopropylethylamine (42.1 ml) was added dropwise

drop at about 10 ° C, and the mixture was stirred for about 3 hours. Water (180 ml) was added, and the organic layer was separated and washed with a mixture of 1 N hydrochloric acid (9 ml) and water (90 ml), then with 10% aqueous sodium chloride solution (198 ml) The organic layer was concentrated under reduced pressure, methanol (180 ml) was added, and then the mixture was again concentrated under reduced pressure to about 187 g. Water (13 ml) was added at approximately 55 ° C, and the mixture was stirred at approximately 10 ° C for about 1 hour. The precipitated crystals were collected by filtration, and washed with a mixture of ethanol (23.1 ml) and water (3.5 ml). The wet crystals were dried under reduced pressure to obtain the title compound (32.1 g, 72.5% yield).

Example 1 (Reference)

10 5- (2-fluorophenyl) -1H-pyrrole-3-carbonitrile

2-Chloro-5- (2-fluorophenyl) -1H-pyrrole-3-carbonitrile (5.0 g, 22.7 mmol), methanol (150 ml) and diisopropylethylamine (3.8 g, 29.5 mmol) were added ) in an autoclave, and the autoclave was purged with nitrogen. 5% palladium on carbon (N.E. CHEMCAT, Standard, 0.5 g) was added. Then, under hydrogen atmosphere (0.1 MPa), the mixture was vigorously stirred at the internal temperature of 15-25 ° C for approximately 4 hours. After purging with nitrogen gas, the catalyst was extracted by filtration, and washed with methanol (15 ml). The organic layer was concentrated under reduced pressure to approximately 13 g. The amount of the content was adjusted to approximately 28 g with ethanol. Water (40 ml) was added dropwise at the internal temperature of 15-25 ° C, and the mixture was stirred at the same temperature for 1 hour. The mixture was cooled to the internal temperature of 0-10 ° C and stirred for 1 hour. The precipitated crystals were collected by filtration, washed with a mixed solution of ethanol and water (1: 2, 15 ml) and dried under reduced pressure at 50 ° C until a constant weight was reached to obtain the compound of the stated (3.8 g, 88% yield).

1H-NMR (300 MHz, DMSO-da) S (ppm): 6.86 (d, J = 1.67 Hz, 1H), 7.22-7.29 (m, 3H), 7.71-7 , 74 (m, 2H), 12.18 (brs, 1H).

elemental analysis (C11H7N2F)

25 Calculated: C: 70.96, H: 3.79, N: 15.05, F: 10.20 Found: C: 70.77, H: 3.86, N: 15.04. melting point: 158.5-160.5 ° C Example 2 (Reference)

5- (2-fluorophenyl) -1H-pyrrole-3-carbonitrile

2-Chloro-5- (2-fluorophenyl) -1H-pyrrole-3-carbonitrile (25.0 g, 113 mmol), ethanol (350 ml) and diisopropylethylamine (19.0 g, 147 mmol) were added in a autoclave, and the autoclave was purged with nitrogen. A 5% palladium on carbon suspension (N.E. CHEMCAT, Standard, 2.5 g) in ethanol (25 ml) was added. Under hydrogen atmosphere, the mixture was vigorously stirred at an internal temperature of 15-25 ° C for about 7 hours. After purging with nitrogen gas, the catalyst was removed by filtration, and washed with ethanol (75 ml). The filtrates were combined and concentrated under reduced pressure to approximately 140 g. Water (200 ml) was added dropwise at the internal temperature of 20-30 ° C, and the mixture was stirred at the same temperature for 0.5 hours. The mixture was cooled to the internal temperature of 0-10 ° C and stirred for 1 hour. The precipitated crystals were collected by filtration, washed with a mixed solution of ethanol and water (1: 2, 75 ml), and dried under reduced pressure at 50 ° C until a constant weight was obtained to obtain the compound of the 40 stated (19.1 g, yield 90.7%). one

1H-NMR (500 MHz, CDCla) S (ppm): 6.84-6.85 (m, 1H), 7.13-7.22 (m, 2H), 7.25-7.29 (m, 1H), 7.38-7.39 (m, 1H), 7.56-7.60 (m, 1H), 9.36 (brs, 1H).

Example 3

5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde

45 5- (2-fluorophenyl) -1H-pyrrole-3-carbonitrile (5.0 g, 26.9 mmol) and THF (33 ml) were added in a four-mouth flask, and the mixture was dissolved at temperature internal 15-25 ° C. Acetic acid (55 ml) and water (11 ml) were added. After purging with nitrogen gas, Raney (Kawaken Fine Chemicals Co., Ltd., NDHT-90, 2.5 ml, wet weight 4 g) was added. Under hydrogen atmosphere, the mixture was stirred vigorously at the internal temperature of 15-25 ° C for about 3 hours. After purging with nitrogen gas, the Raney nickel was filtered off, and washed with ethyl acetate (50 ml). 5 N aqueous sodium hydroxide solution (approximately 180 ml) was added to the filtrate at the internal temperature of 10-35 ° C to adjust the mixture to a pH of 7-8, and the mixture was partitioned. The organic layer was washed with 5% aqueous sodium bicarbonate solution (25 ml) and 5% brine (25 ml). Water (25 ml) was added to the organic layer, and the mixture was adjusted with 6 N hydrochloric acid at a pH of 3.0-3.5 at

internal temperature of 15-25 ° C. After stirring overnight, the mixture was partitioned. The organic layer was washed with 5% brine (25 ml), concentrated under reduced pressure to approximately 18 g. After increasing the internal temperature to 65-70 ° C, the mixture was cooled to the internal temperature of 45-55 ° C, and also stirred for 1 hour. After cooling to the internal temperature of 15-25 ° C, n-heptane (25 ml) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. In addition, the mixture was stirred at the internal temperature of 0-10 ° C for 1 hour. The precipitated crystals were collected by filtration, washed with ethyl acetate: n-heptane (1: 2, 15 ml), and dried under reduced pressure at 50 ° C until a constant weight was obtained to obtain the title compound (23.9 g, yield 78%).

1H-NMR (300 MHz, DMSO-da) S (ppm): 6.91 (d, J = 1.6 Hz, 1H), 7.21-7.31 (m, 3H), 7.75-7 , 80 (m, 2H), 9.76 (s, 1H), 10 12.17 (brs, 1H).

elemental analysis (C-nHaNOF)

Calculated: C: 69.83, H: 4.26, N: 7.40, O: 8.46, F: 10.04 Found: C: 69.91, H: 4.27, N: 7.33 melting point: 123.0-126.0 ° C 15 Example 4

5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldel'ndo

5- (2-fluorophenyl) -1H-pyrrole-3-carbaldel'ndo (5.00 g, 26.43 mmol), N, N-dimethylpyridine-4-amine (0.65 g, 5.29 mmol) were added ), diisopropylethylamine (4.78 g, 37.00 mmol) and acetonitrile (18.5 ml) in a four-mouth flask, and a solution of pyridine-3-sulfonyl chloride (5.63 g, 31.71) mmol) in acetonitrile (5 ml). Acetonitrile 20 (1.5 ml) was also added, and the mixture was stirred at the internal temperature of 40-50 ° C for 1.5 hours. The internal temperature cooled to

30 ° C, and water (15 ml) was added dropwise. The mixture was adjusted to pH 4-5 with 0.5 N chlortndric acid. Initiating crystals (2.5 mg) of the above compound were added, and then water (approximately 30 ml) was added dropwise. After stirring at the internal temperature of 20-30 ° C for 0.5 hours, the internal temperature was cooled to 0-10 ° C, and the mixture was stirred for 1 hour. The precipitated crystals were collected by filtration, washed with a cold mixed solution of acetonitrile and water (1: 2, 7.5 ml), and water (7.5 ml x 2), and dried under reduced pressure at 50 ° C until a constant weight was achieved to obtain the statement compound (7.57 g, 86.7% yield). one

1H-NMR (300 MHz, CDCla) S (ppm): 6.68 (d, J = 1.7 Hz, 1H), 7.01-7.05 (m, 1H), 7.16-7.18 (m, 2H), 7.37-7.40 (m, 1H), 7.45-7.51 (m, 1H), 7.69-7.72 (m, 1H), 8.15 (d , J = 1.8 Hz, 1H), 8.58 (d, J = 1.7 Hz, 1H), 8.82 (dd, J = 4.8, 1.5 Hz, 30 1H), 9, 90 (s, 1 H).

elemental analysis (C16H11N2O3SF)

Calculated: C: 58.17, H: 3.36, N: 8.48, O: 14.53, S: 9.71, F: 5.75 Found: C: 58.32, H: 3.46 , N: 8.54, S: 9.76, F: 5.62. melting point: 106-108 ° C 35 Example 5

1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl] -N-methylmethanamine fumarate

To a flask purged with nitrogen, N, N-dimethylacetamide (108 ml) and sodium borohydride (3.06 g, 81.74 mmol) were added, and the mixture dissolved (solution A). To another flask purged with nitrogen was added 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-carbaldel'ndo (60.00 g, 181.64 mmol) and methanol (300 ml), and then a solution (18.34 g, 236.13 mmol) of 40% methylamine in methanol was added dropwise at room temperature. The mixture was stirred more at the internal temperature of 20-30 ° C for 30 minutes. The internal temperature was cooled to -10 ° C, and the previously prepared solution A was added dropwise to the internal temperature of no more than 0 ° C. N, N-dimethylacetamide (12 ml) was added, and the mixture was stirred at an internal temperature of -10 to 0 ° C for 1 hour. 1N HCl (360 ml) was added dropwise at the internal temperature of no more than 20 ° C, and the mixture was stirred at the internal temperature of 10-20 ° C for 30 minutes. 12.5% aqueous ammonia (240 ml), ethyl acetate (600 ml) and water (180 ml) were added, and the mixture partitioned. Water (240 ml) and ethyl acetate (360 ml) were added to the aqueous layer and the mixture was extracted again. The organic layers were combined and washed twice with 5% brine (360 ml). The organic layer was concentrated to approximately 253 g, and N, N-dimethylacetamide (480 ml) was added. The mixture was heated to the internal temperature of 50 ° C, and fumaic acid (21.08 g, 181.64 mmol) was added. The mixture was stirred at the internal temperature of 50 ° C for 30 minutes, cooled, and stirred at room temperature for 1 hour. The precipitated crystals were filtered, washed with a mixed solution of ethyl acetate and N, N-dimethylacetamide (1: 2, 90 ml), and then with ethyl acetate (120 ml), and dried under reduced pressure at 50 ° C to obtain a crude product (62.73 g).

The crude product (55.00 g) obtained above was suspended in a mixed solution of methanol and water (7: 3, 550 ml), and dissolved at the internal temperature of 60-65 ° C. Activated carbon SHIRASAGI A (registered trademark, 2.75 g) was added, and the mixture was stirred for 10 minutes, filtered and washed with a mixed solution of methanol and water (7: 3, 110 ml). The combined filtrate was heated to the internal temperature of approximately 55 ° C, cooled 5 to room temperature, and further stirred at the internal temperature of 0-10 ° C for 1 hour. The precipitated crystals were filtered, washed with a mixed solution of methanol and water (1: 1, 110 ml), and dried under reduced pressure at 50 ° C to obtain the title compound (47.50 g, yield 64 , 6%).

1H-NMR (300 MHz, DMSO-d6), S (ppm): 2.46 (s, 3H), 3.92 (s, 2H), 6.49 (s, 2H), 6.51 (d, J = 1.7 Hz, 1H), 7.08-7.13 (m, 1H), 7.20-7.26 (m, 2H), 7.49-7.54 (m, 1H), 7 , 60-7.64 (m, 1H), 7.78 (s, 1H), 7.89 (dd, J = 8.2, 1.6 Hz, 1H), 8.57 (d, 10 J = 2.2 Hz, 1H), 8.89 (d, J = 4.7 Hz, 1H), 10.81 (brs, 2H), 1H not detected.

elemental analysis (C21H20N3O6SF)

Calculated: C: 54.66, H: 4.37, N: 9.11, O: 20.80, S: 6.95, F: 4.12.

Found: C: 54.68, H: 4.31, N: 9.07, S: 7.00, F: 4.15. melting point: 203-205 ° C 15 Example 6

1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl] -N-methylmethanamine fumarate

N, N-dimethylacetamide (18 ml) and sodium borohydride (0.52 g, 13.6 mmol) were added in a nitrogen purged flask, and the mixture was dissolved (solution A). In another nitrogen-purged flask, 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-carbaldehyde (10.0 g, 30.3 mmol) and methanol (50 ml) were added , and then a solution (3.06 g, 39.4 mmol) of 40% methylamine in methanol was added dropwise at room temperature, and the mixture was further stirred at an internal temperature of 20-30 ° C for 30 minutes. The internal temperature was lowered to 5 ° C, and the solution A previously prepared was added dropwise at the internal temperature of 0-10 ° C. N, N-dimethylacetamide (2 ml) was added, and the mixture was stirred at an internal temperature of 0-10 ° C for 1 hour. 1N HCl (70 ml) was added dropwise, at an internal temperature of no more than 20 ° C, and the mixture was stirred at the internal temperature of 25-25-25 ° C for 30 minutes. 12.5% aqueous ammonia (60 ml) and ethyl acetate (100 ml) were added to

Partition the mixture. 5% brine (50 ml) and ethyl acetate (50 ml) were added to the aqueous layer and the mixture was extracted again. The organic layers were combined and washed twice with 5% brine (60 ml). The organic layer was concentrated to about 25 ml, ethyl acetate (70 ml) was added, and the mixture was concentrated again to about 38.0 ml. N, N-dimethylacetamide (60 ml) was added, the mixture was heated to internal temperature 30 of 45 ° C, and fumaric acid (3.51 g, 30.3 mmol) was added. After stirring at the internal temperature of 40-50 ° C for 30 minutes, ethyl acetate (30 ml) was added dropwise, and the mixture was stirred at the internal temperature of 40-50 ° C for 30 minutes. The mixture was cooled, and stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, and washed with a mixed solution of ethyl acetate and N, N-dimethylacetamide (1: 1, 15 ml), and then with ethyl acetate (30 ml) to obtain a crude product ( wet product 35).

The crude product (wet product) obtained above, was suspended in a mixed solution of methanol and water (1: 1, 100 ml), and dissolved at the internal temperature of 60-70 ° C. SHIRASAGI A activated carbon (registered trademark, 0.30 g) was added, and the mixture was stirred for 10 minutes, filtered, and washed with a mixed solution of methanol and water (1: 1, 20 ml). The combined filtrate was dissolved again at the internal temperature of about 55-65 40 ° C, cooled to room temperature, and further stirred at the internal temperature of 0-10 ° C for 1 hour. The

precipitated crystals were collected by filtration, washed with a mixed solution of methanol and water (1: 1.20 ml), and dried under reduced pressure at 50 ° C to obtain the compound of the statement (10.07 g, yield of 72.1%)

1H-NMR (500 MHz, DMSO-d6) S (ppm): 2.44 (s, 3H), 3.87 (s, 2H), 6.48-6.49 (m, 3H), 7.09 -7.12 (m, 1H), 7.20-7.25 45 (m, 2H), 7.50-7.55 (m, 1H), 7.60-7.63 (m, 1H), 7.74-7.75 (m, 1H), 7.87-7.89 (m, 1H), 8.55-8.56 (m, 1H), 8.87-8.89 (m,

1H), 3H not detected.

Example 7 (Reference)

(1--) S- {3-cyano-5- (2-fluorophenyl) -1H-pyrrol-2-yl} benzene carbodithioate

image34

5

10

fifteen

twenty

25

30

35

To a solution of [2- (2-fluorophenyl) -2-oxoethyl] propanedinitrile (30.1 g, 149 mmol) in methanol (200 ml), thiobenzoic acid (28.2 ml, 238 mmol) and triethylamine ( 2.08 ml, 14.9 mmol), and the mixture was stirred at 60-70 ° C for 2 hours. The mixture was allowed to cool, and methanol (300 ml) and water (50 ml) were added at approximately 50 ° C. After stirring at room temperature for 1 hour and at 0-10 ° C for 1 hour, the crystals were collected by filtration, washed with a mixed solution cooled with ice (120 ml) of water / methanol (4: 1) and dried under reduced pressure at 50 ° C to obtain the compound of the sentence (38.6 g, 80% yield).

1H-NMR (300 MHz, TMS, DMSO-da) S (ppm): 12.9 (brs, 1H), 8.06-8.03 (m, 2H), 7.82-7.77 (m, 2H), 7.69-7.64 (t, J = 7.6 Hz, 2H), 7.41-7.32 (m, 3H), 7.09 (s, 1H).

(2) 5- (2-fluorophenyl) -1H-pyrrole-3-carbonitrile

image35

Under a stream of nitrogen, a catalyst Raquel (76 g), N, N-dimethylacetamide (206 ml) and morpholine (15.6 ml, 0.18 mol) was placed in a reactor, and the mixture was stirred at temperature ambient. While maintaining the internal temperature at no more than 40 ° C, a solution of S- {3-cyano-5- (2- fluorophenyl) -1H-pyrrole-2-yl} benzenedicarbonate (slowly added dropwise) 38.6 g, 0.12 mol) in N, N-dimethylacetamide (180 ml). The mixture was heated under reflux at the internal temperature of 100-110 ° C for 1 hour. After allowing the mixture to cool to room temperature, the Raney catalyst was filtered off and washed with ethyl acetate (120 ml). Ethyl acetate (280 ml) and 10% brine (600 ml) were added to the filtrate, and the mixture was extracted and partitioned. The aqueous layer was extracted 3 times with ethyl acetate (200 ml, 100 ml, 100 ml), the organic layers were combined, and washed with water (1 L). Ethanol (120 ml) was added to the concentrate, water (240 ml) was added while stirring with heating at 60-65 ° C, and the mixture was further stirred at the same temperature for 1 hour. The mixture was allowed to cool to 30 ° C or less, and stirred at 0-10 ° C for 1 hour. The crystals were collected by filtration, and washed with ice-cold mixed solution (40 ml) of water / ethanol (1: 2), and dried under reduced pressure at 50 ° C until a constant weight was reached to obtain the compound of the statement (17.6 g, yield 79%).

1H-NMR (DMSO-d6, TMS, 300 MHz) S (ppm): 9.3 (br, 1H), 7.6-7.5 (m, 1H), 7.4-7.3 (m, 1H), 7.3-7.1 (m, 3H), 6.84 (d, J = 1.7 Hz, 1H).

Example 8 (Reference)

(1) 2,2'-disulfanodiylbis [5- (2-fluorophenyl) -1H-pyrrole-3-carbonitrile]

image36

[2- (2-fluorophenyl) -2-oxoethyl] propanedinitrile (5.05 g, 25 mmol), methanol (50.5 ml), thioacetic acid (1.79 ml, 25 mmol) and triethylamine (0.7 ml , 5 mmol) were loaded into a four-ml 100 ml flask, and the mixture was heated under reflux for 10 hours. Water (10.2 ml) was added, and the mixture was refluxed for 1 hour. The mixture was allowed to cool and cooled with ice, and the precipitated crystals were collected by filtration and washed by spraying a mixed solution (20.2 ml) cooled with water / methanol ice (1:10), and dried under pressure. reduced to 50 ° C to obtain the compound of the statement (4.64 g, 85% yield).

(2) 5- (2-fluorophenyl) -1H-pyrrole-3-carbonitrile

image37

Under a stream of nitrogen, Raquel (12.6 g), N, N-dimethylacetamide (30 ml), morpholine (1.36 ml, 15.6 mmol) and a 2,2'-dithiobis solution [ 5- (2-fluorophenyl) -1H-pyrrole-3-carbonitrile] (4.50 g, 10.4 mmol) in N, N-

dimethylacetamide (15 ml) in a 100 ml four-mouth flask, and the mixture was heated under reflux at 105 ° C for 5.5 hours. The reaction mixture was cooled, and the catalyst was extracted by filtration, and washed with N, N-dimethylacetamide and ethyl acetate, in that order. 5% brine was added to the filtrate and washing products, the mixture was partitioned and the aqueous layer was extracted 3 times with ethyl acetate. The organic layers were combined, washed with 5% brine, and concentrated to dryness under reduced pressure. Ethanol (22.5 ml) was added to the residue, and the mixture was dissolved by heating. Water (45 ml) was added to cause crystallization. The slurry was heated under reflux for 1 hour, and allowed to cool and cooled with ice, and the crystals were collected by filtration. The crystals were washed by spraying a mixed solution (10 ml) cooled with water / ethanol ice (1: 2) and dried under reduced pressure at 50 ° C to obtain the compound of the statement (3.45 g, yield 85). %).

1H-NMR (DMSO-da, TMS, 300 MHz) S (ppm): 9.3 (br, 1H), 7.6-7.5 (m, 1H), 7.4-7.3 (m, 1H), 7.3-7.1 (m, 3H), 6.84 (d, J = 1.7 Hz, 1H).

mass spectrometna (EI, m / z) (relative intensity): 186 (M +, 100), 158 (20), 132 (11). elemental analysis (C11H7N2F)

15 Calculated: C, 70.96; H, 3.79; N, 15.05.

Found: C, 70.69; H, 3.89, N, 14.86

Example 9 (Reference)

2- (methylsulfanyl) -5-phenyl-1H-pyrrole-3-carbonitrile

image38

20 (2-phenyl-2-oxoethyl) propanedinitrile (2.0 g, 10.9 mmol), acetic acid (3.26 g, 54.3 mmol) and methanol (20 ml) were loaded into a reactor; 15% aqueous sodium thiomethoxide solution (7.6 g) was added dropwise, and the mixture was heated under reflux for 6 hours. The reaction mixture was cooled to room temperature, and stirred at room temperature for 1 hour and at 0-10 ° C for 1 hour. The crystals were collected by filtration, washed with a mixed solution cooled with ice (2 ml) of water / methanol (1: 1) and dried under reduced pressure at 50 ° C to obtain the compound of the statement (2.1 g, yield 90%).

1H-NMR (300 MHz, TMS, DMSO-d6) S (ppm): 12.5 (brs, 1H), 7.72-7.69 (m, 2H), 7.43-7.38 (m, 2H), 7.30-7.28 (m, 1H), 6.98 (s, 1H), 2.52 (s, 3H).

Example 10 (Reference)

5- (2-methylphenyl) -2- (methylsulfanyl) -1H-pyrrole-3-carbonitrile

30

[2- (2-Methylphenyl) -2-oxoethyl] propanedinitrile (2.0 g, 10.9 mmol), acetic acid (3.26 g, 54.3 mmol) and methanol (20ml) were loaded into a reactor; 15% aqueous sodium thiomethoxide solution (7.6 g) was added dropwise, and the mixture was heated under reflux for 6 hours. The reaction mixture was cooled to room temperature, and stirred at room temperature for 1 hour and at 0-10 ° C for 1 hour. The crystals were collected by filtration, and washed with a mixed solution cooled with ice (2 ml) of water / methanol (1: 1). The crystals were dried under reduced pressure at 50 ° C to obtain the title compound (1.8 g, 78% yield). one

1H-NMR (300 MHz, TMS, CDCla) S (ppm): 8.5-8.7 (brs, 1H), 7.2-7.3 (m, 4H), 6.51 (d, J = 2.8 Hz, 1H), 2.50 (s, 3H), 2.4 (s, 3H).

mass spectrometna (EI, m / z) 228 [M +]

40 elementary analysis (C13H12N2S)

image39

Calculated: C, 68.39; H, 5.30; N, 12.27; S, 14.04. Found: C, 68.30; H, 5.26; N, 12.30; S, 14.11. melting point 148-149 ° C Example 11 (Reference)

5 5-tert-butyl-2- (metMsulfanyl) -1H-pyrrole-3-carbonitrile

image40

[2- (tert-Butyl) -2-oxoethyl] propanedinitrile (1.0 g, 6.1 mmol), acetic acid (1.1 g, 18.3 mmol) and methanol (10 ml) were loaded into a reactor ; 15% aqueous sodium thiomethoxide solution (5.7 ml, 12.2 mmol) was added dropwise, and the mixture was heated under reflux for 1 hour. Water and ethyl acetate were added to the reaction mixture, the

The mixture was partitioned, and the organic layer was washed with saturated aqueous sodium bicarbonate. The organic layer was concentrated, a mixture of methanol and water was added to the concentrated residue, and the mixture was stirred at room temperature for 1 hour. The crystals were collected by filtration, washed with a mixed solution cooled with ice (1 ml) of water / methanol (1: 1), and dried under reduced pressure at 50 ° C, to obtain the compound of the statement (1, 1 g, 84% yield).

15 1H-NMR (300 MHz, TMS, CDCla) S (ppm): 8.3 (brs, 1H), 6.18 (d, J = 2.9 Hz, 1H), 2.47 (s, 3H) , 1.29 (s, 9H).

High Resolution Mass Spectrometna (EI, m / z) (C10H14N2S)

Calculated 194.0878 Found: 194.0877 Example 12 (Reference)

5- (3-methoxyphenyl) -2- (methylsulfanyl) -1H-pyrrole-3-carbonitrile

image41

[2- (3-Methoxyphenyl) -2-oxoethyl] propanedinitrile (1.0 g, 4.67 mmol), acetic acid (0.84 g, 14.0 mmol) and methanol (10 ml) were loaded into a reactor ; 15% aqueous sodium thiomethoxide solution (4.35 ml, 9.33 mmol) was added dropwise, and the mixture was heated under reflux for 6 hours. The reaction mixture was cooled to room temperature, water (5 ml) was added, and the mixture was stirred at room temperature for 1 hour and at 0-10 ° C for 1 hour. The crystals were collected by filtration, washed with a mixed solution cooled with ice (2 ml) of water / methanol (1: 1), and dried under reduced pressure at 50 ° C to obtain the compound of the statement (0.74 g, 70% yield):

1H-NMR (300 MHz, TMS, CDCla) S (ppm): 8.90 (brs, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 7 , 7 Hz, 1H), 6.96-6.97 30 (m, 1H), 6.86 (dd, J = 5.4 and 2.4 Hz, 1H), 6.68 (d, J = 2 , 8 Hz, 1H), 3.83 (s, 3H), 2.52 (s, 3H).

High resolution mass spectromet (EI, m / z) (C- ^ H - ^^ OS)

Calculated 244.0670

Found 244.0664

35

image42

[2- (4-Bromophenyl) -2-oxoethyl] propanedinitrile (1.5 g, 5.70 mmol), acetic acid (1.7 g, 28.5 mmol) and methanol (15 ml) were loaded into a reactor, 15% aqueous sodium thiomethoxide solution (10.7 ml, 22.8 mmol) was added dropwise, and the mixture was heated under reflux for 5 hours. The reaction mixture was cooled to room temperature, and the mixture was stirred at room temperature for 1 hour and at 0-10 ° C for 1 hour. The crystals were collected by filtration, washed with ice-cold mixed solution (2 ml) of water / methanol (1: 1) and dried under reduced pressure at 50 ° C to obtain the title compound (1.14 g, 68% yield).

10 1H-NMR (300 MHz, TMS, CDCla) S (ppm): 8.7 (brs, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 6.7 Hz, 2H), 6.69 (d, J =

2.3 Hz, 1 H), 2.54 (s, 3H).

High resolution mass spectromet (EI, m / z) (C- ^ HgBr ^ S)

Calculated 291.9670 Found 291.9684 15 Example 14 (Reference)

2- (methylsulfanyl) -5-naphthalen-2-yl-1H-pyrrole-3-carbonitrile

image43

(2-Naphthalen-2-yl-2-oxoethyl) propanedinitrile (1.0 g, 4.25 mmol), acetic acid (1.27 g, 21.3 mmol) and methanol (20 ml) were loaded into a reactor ; 15% aqueous sodium thiomethoxide solution (9.8 ml, 21.3 mmol) was added dropwise, and the mixture was heated under reflux for 5 hours. The reaction mixture was cooled to room temperature, and stirred at room temperature for 1 hour and at 0-10 ° C for 1 hour. The crystals were collected by filtration, washed with ice-cold mixed solution (2 ml) of water / methanol (1: 1), and dried under reduced pressure at 50 ° C to obtain the title compound (0.97 g , 86% yield).

1H-NMR (300 MHz, TMS, CDCla) S (ppm): 8.86 (brs, 1H), 7.83-7.90 (m, 4H), 7.47-7.59 (m, 3H) , 6.82 (d, J = 2.7 Hz, 25 1H), 2.56 (s, 3H).

High resolution mass spectrometna (EI, m / z) (C16H12N2S)

Calculated 264.0721 Found 264.0715 Example 15 (Reference)

30 (1) 5- (4-fluorophenyl) -2- (methylsulfanyl) -1H-pyrrole-3-carbonitrile

image44

[2- (4-fluorophenyl) -2-oxoethyl] propanedinitrile (4.0 g, 19.8 mmol), acetic acid (6.0 g, 99.0 mmol) and methanol (40 ml), se

loaded into a reactor; 15% aqueous sodium thiomethoxide solution (14.0 ml, 29.7 mmol) was added dropwise, and the mixture was heated under reflux for 6 hours. The reaction mixture was cooled to room temperature, and stirred at room temperature for 1 hour and at 0-10 ° C for 1 hour. The crystals were collected by filtration, washed with ice-cold mixed solution (2 ml) of water / methanol (1: 1), and dried under reduced pressure at 50 ° C to obtain the title compound (3.6 g, yield 78%).

1H-NMR (300 MHz, TMS, DMSO-da) S (ppm): 12.5 (brs, 1H), 7.77-7.72 (m, 2H), 7.26 (t, J = 8, 9 Hz, 2H), 6.96 (s, 1H), 2.51 (s, 3H).

elemental analysis (C12H9FN2S)

Calculated: C, 62.05; H, 3.91; N, 12.06; S, 13.80; F, 8.18.

10 Found: C, 61.90; H, 3.75; N, 12.30; S, 13.79; F, 8.17. melting point 187-188 ° C

(2) 5- (4-fluorophenyl) -2- (methylsulfonyl) -1H-pyrrole-3-carbonitrile

image45

Under ice cooling, to a solution of 5- (4-fluorophenyl) -2- (methylsulfanyl) -1H-pyrrol-3-carbonitrile (2 g, 8.61 15 mmol) in ethyl acetate (20 ml), m-Chloroperbenzoic acid (3.26 g, 19 mmol) added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was washed successively with aqueous sodium sulphite solution, with saturated aqueous sodium bicarbonate and with water. The organic layer was concentrated to obtain the compound of the sentence (2.0 g, 88% yield).

1H-NMR (300 MHz, TMS, DMSO-d6) S (ppm): 7.90-7.85 (m, 2H), 7.32 (t, J = 8.9 Hz, 2H), 7.23 (s, 1H), 3.34 (s, 3H).

20 Example 16 (Reference)

2 - [(2,4-dichlorophenyl) sulfanyl] -5-phenyl-1H-pyrrole-3-carbonitrile

image46

(2-phenyl-2-oxoethyl) propanedinitrile (1.0 g, 5.43 mmol), triethylamine (0.08 ml, 0.543 mmol), methanol (10 ml) and 2,4-dichlorobenzenethiol (1.46 g, 8.15 mmol) were loaded into a reactor, and the mixture was stirred at 40 ° C for 4 hours.

25 The mixture was allowed to cool and stirred at room temperature for 1 hour. The crystals were collected by filtration, and washed with a mixed solution cooled with ice (1 ml) of water / methanol (1.1). The crystals were dried under reduced pressure at 50 ° C to obtain the title compound (1.46 g, yield 78%).

1H-NMR (300 MHz, TMS, CDCla) S (ppm): 9.0 (brs, 1H), 7.48-7.42 (m, 6H), 7.15-7.14 (m, 1H) , 6.92 (d, J = 8.5 Hz, 1H), 6.84 (d, J = 2.8 Hz, 1H).

30 mass spectrometna (EI, m / z) 344 [M +].

high resolution mass spectrometna (C17H10C12N2S)

Calculated 343,9942

Found 343.9944

35

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25

30

image47

(2-phenyl-2-oxoethyl) propanedinitrile (1.0 g, 5.43 mmol), triethylamine (0.08 ml, 0.543 mmol), methanol (10 ml) and 2- naphthalenediol (1.3 g, 8, 15 mmol) were loaded into a reactor, and the mixture was stirred at 40 ° C for 0.5 hour. Water (2 ml) was added, and the mixture was stirred at room temperature for 1 hour. The crystals were collected by filtration, washed with ice-cold mixed solution (1 ml) of water / methanol (1: 1), and dried under reduced pressure at 50 ° C to obtain the title compound (0.63 g , 35% yield).

1H-NMR (300 MHz, TMS, CDCl3) S (ppm): 9.0 (brs, 1H), 7.8-7.3 (m, 12H), 6.80 (d, J = 2.8 Hz , 1 HOUR)

High Resolution Mass Spectrometna (EI, m / z) (C21H14N2S)

Calculated 326.0878

Found 326.0883

melting point 93.0-94.4 ° C

Example 18 (Reference)

2 - [(2-aminophenyl) sulfanyl] -5-phenyl-1H-pyrrole-3-carbonitrile

(2-Phenyl-2-oxoethyl) propanedinitrile (5.0 g, 27.1 mmol), triethylamine (0.4 ml, 2.71 mmol), methanol (50 ml) and o-aminobenzenethiol (5.0 ml, 40.7 mmol) were loaded into a reactor, and the mixture was stirred at 40 ° C for 1 hour. The reaction mixture was concentrated, and the concentrate was purified by silica gel column chromatography to obtain the title compound (2.3 g, 29% yield).

1H-NMR (300 MHz, TMS, CDCl3) S (ppm): 9.60 (brs, 1H), 7.56-7.53 (m, 1H), 7.37-7.35 (m, 4H) , 7.27-7.20 (m, 2H), 6.85-6.60 (m, 2H), 6.60 (d, J = 2.9 Hz, 1H), 4.5-3.50 (br, 2H).

high resolution mass spectrometna (EI, m / z) (C17H13N3S)

Calculated 291.0830

Found 291.0826

melting point 159.0-160.0 ° C

Example 19 (Reference)

2 - [(2-bromophenyl) sulfanyl] -5-phenyl-1H-pyrrole-3-carbonitrile

(2-Phenyl-2-oxoethyl) propanedinitrile (5.0 g, 27.1 mmol), triethylamine (0.4 ml, 2.71 mmol), methanol (50 ml) and o-

image48

image49

Bromobenzenethiol (5.0 ml, 40.7 mmol) was loaded into a reactor, and the mixture was stirred at 40 ° C for 1 hour. The mixture was allowed to cool, and stirred at room temperature for 1 hour. The crystals were collected by filtration, washed with ice-cold mixed solution (5 ml) of water / methanol (1: 1), and dried under reduced pressure at 50 ° C to obtain the title compound (6.9 g , 72% yield).

5 1H-NMR (300 MHz, TMS, CDCla) S (ppm): 9.2 (brs, 1H), 7.55-7.40 (m, 6H), 7.19-7.06 (m, 2H ), 6.90-6.86 (m, 1H),

6.81 (d, J = 2.8 Hz, 1H).

mass spectrometna (EI, m / z) 354 [M +]

high resolution mass spectrometna (C ^ H-i-iBr ^ S]

Calculated 353.9826

10 Found 353.9816

melting point 126.0-127.0 ° C

Example 20 (reference)

2 - [(3-bromophenyl) sulfanyl] -5-phenyl-1H-pyrrole-3-carbonitrile

image50

15 (2-phenyl-2-oxoethyl) propanedinitrile (1.0 g, 5.43 mmol), triethylamine (0.08 ml, 0.543 mmol), methanol (10 ml) and m-bromobenzenethiol (1.46 g, 8 , 15 mmol) were loaded into a reactor, and the mixture was stirred at 40 ° C for 4 hours. The mixture was allowed to cool, and stirred at room temperature for 1 hour. The crystals were collected by filtration, washed with ice-cold mixed solution (1 ml) of water / methanol (1: 1), and dried under reduced pressure at 50 ° C to obtain the title compound (1.6 g , 80% yield).

20 1H-NMR (300 MHz, TMS, CDCla) S (ppm): 9.0 (brs, 1H), 7.49-7.42 (m, 4H), 7.35-7.33 (m, 3H ), 7.15-7.14 (m, 2H),

6.80 (d, J = 2.8 Hz, 1H).

mass spectrometna (EI, m / z) 354 [M +]

high resolution mass spectrometna (C ^ H-i-iBr ^ S)

Calculated 353.9826

25 Found 353.9824

melting point 141.0-142.0 ° C

Example 21 (Reference)

5-phenyl-2- (pyridin-4-ylsulfanyl) -1H-pyrrole-3-carbonitrile

image51

30 (2-phenyl-2-oxoethyl) propanedinitrile (1.0 g, 5.43 mmol), methanol (10 ml) and 4-mercaptopyridine (1.2 g, 8.15 mmol) were loaded into a reactor, and The mixture was heated under reflux for 7 hours. The mixture was allowed to cool and stirred at room temperature for 1 hour. The crystals were collected by filtration, washed with ice-cold mixed solution (1 ml) of water / methanol (1: 1), and dried under reduced pressure at 50 ° C to obtain the title compound (1.2 g , 80% yield).

35 1H-NMR (300 MHz, TMS, DMSO-d6) S (ppm): 13.0 (brs, 1H), 8.43 (d, J = 6.2 Hz, 2H), 7.78 (d, J = 7.2 Hz, 2H), 7.47

7.29 (m, 4H), 7.05 (d, J = 6.5 Hz, 2H)

high resolution mass spectrometna (EI, m / z) (C16H11N3S)

Calculated 277.0674

Found 277.0678

melting point 172-174 ° C.

Example 22 (Reference)

2 - [(4-aminophenyl) sulfanyl] -5-phenyl-1H-pyrrole-3-carbonitrile

image52

(2-phenyl-2-oxoethyl) propanedinitrile (1.0 g, 5.43 mmol), methanol (10 ml) and p-aminobenzenethiol (1.26 g, 8.15 mmol) were loaded into a reactor, and the mixture was heated under reflux for 4 hours. The mixture was allowed to cool, 10 water (5 ml) was added, and the mixture was stirred at room temperature for 1 hour. The crystals were collected by filtration, washed with ice-cold mixed solution (1 ml) of water / methanol (1: 1), and dried under reduced pressure at 50 ° C to obtain the title compound (1.05 g , 66% yield).

1H-NMR (300 MHz, TMS, DMSO-d6) S (ppm): 7.76 (d, J = 7.2 Hz, 2H), 7.44 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.4 Hz, 1H), 7.21 (d, J = 8.6 Hz, 2H), 7.06 (s, 1H), 6.57 (d, J = 8 , 6 Hz, 2H), 5.40 (s, 2H).

15 elementary analysis (C17H13N3S)

Calculated: C, 70.08; H, 4.50; N, 14.42, S, 11.00.

Found: C, 69.93; H, 4.43; N, 14.49; S, 11.05.

melting point 146-147 ° C

Example 23 (Reference)

20 2 - [(2-fluorophenyl) sulfanyl] -5-phenyl-1H-pyrrole-3-carbonitrile

image53

(2-phenyl-2-oxoethyl) propanedinitrile (1.0 g, 5.43 mmol), triethylamine (0.08 ml, 0.543 mmol), methanol (10 ml) and 2-fluorobenzenethiol (1.04 g, 8, 15 mmol) were loaded into a reactor, and the mixture was stirred at 40 ° C for 4 hours. The mixture was allowed to cool, and stirred at room temperature for 1 hour. The crystals were collected by filtration, washed with ice-cold mixed solution (1 ml) of water / methanol (1: 1), and dried under reduced pressure at 50 ° C to obtain the title compound (1.1 g, 69% yield). one

1H-NMR (300 MHz, TMS, DMSO-d6) S (ppm): 12.9 (brs, 1H), 7.77 (d, J = 7.2 Hz, 2H), 7.43 (t, J = 7.1 Hz, 2H), 7.347.29 (m, 3H), 7.21-7.17 (m, 2H), 6.93 (t, J = 7.7 Hz, 1H).

mass spectrometna (EI, m / z) 294 [M +].

30 high resolution mass spectrometna (C17H11FN2S)

Calculated 294.0627

Found 294.0620

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25

30

35

image54

(2-Phenyl-2-oxoethyl) propanedinitrile (1.0 g, 5.43 mmol), triethylamine (0.08 ml, 0543 mmol), methanol (10 ml) and 4- nitrobenzenethiol (1.46 g, 8, 15 mmol) were loaded into a reactor, and the mixture was stirred at 40 ° C for 4 hours. The mixture was allowed to cool and stirred at room temperature for 1 hour. The crystals were collected by filtration, washed with ice-cold mixed solution (1 ml) of water / methanol (1: 1), and dried under reduced pressure at 50 ° C to obtain the title compound (1.7 g , 80% yield).

1H-NMR (300 MHz, TMS, DMSO-da) S (ppm): 13.1 (brs, 1H), 8.20 (d, J = 9.0 Hz, 2H), 7.78 (d, J = 7.2 Hz, 2H), 7.45 (t, J = 6.5 Hz, 2H), 7.33-7.30 (m, 4H).

High resolution mass spectrometna (EI, m / z) (C17H11N3O2S)

Calculated 321,0572 Found 321.0566 melting point 230-231 ° C Example 25 (Reference)

[(3-Cyano-5-phenyl-1H-pyrrol-2-yl) sulfanyl] acetic acid

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(2-Phenyl-2-oxoethyl) propanedinitrile (1.0 g, 54.3 mmol), methanol (150 ml) and thioglycolic acid (6.0 g, 52.6 mmol) were charged in a reactor, and the mixture It was heated under reflux for 0.5 hours. The mixture was allowed to cool and stirred at room temperature for 0.5 hours and under ice cooling for 0.5 hours. The crystals were collected by filtration. The wet crystals were washed with ethyl acetate (60 ml), and dried under reduced pressure at 50 ° C to obtain the title compound (8.8 g, 60% yield).

1H-NMR (300 MHz, TMS, DMSO-d6) S (ppm): 7.60 (d, J = 8.0 Hz, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.26-7.21 (m, 1H), 6.66 (s, 1H), 2.51 (s, 2H).

High Resolution Mass Spectrometna (FAB) (C13H10N2O2S)

Calculated 257.0835 [M-H] '

Found 257.0390 [M-H] ‘

Example 26 (Reference)

4- (2-fluorophenyl) -2- (iminomethyl) -4-oxobutanonitrile

[2- (2-fluorophenyl) -2-oxoethyl] propanedinitrile (3.00 g, 14.8 mmol) and THF (30 ml) were weighed, placed in a 50 ml flask and dissolved. The mixture was purged with an inert gas, 5% Pd-C (1.20 g, corresponding to 2 mol% based on Pd) was added, and washed with THF (5 ml). Then, the mixture was purged with hydrogen, and reacted at room temperature for 4 hours (catalytic reduction was performed until the starting material was less than 2%). The catalyst was extracted by filtration, and washed with THF (15 ml), and concentrated to dryness under reduced pressure to obtain a crude product (3.32 g) of the title compound. From this, 2.44 g were suspended in ethyl acetate (5 ml) n-hexane (5 ml), and the suspension was stirred for 0.5 hours. The suspension was filtered by suction, washed with ethyl acetate (2 ml) / n-hexane (2 ml), and dried under reduced pressure at 50 ° C to obtain the compound of the statement (1.47 g, yield of 65.9%).

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1H-NMR (300 MHz, DMSO-da) S (ppm): 3.66 (d, J = 2.3 Hz, 2H), 6.37 (m, 2H), 6.79 (t, J = 11 , 1 Hz, 1H), 7.28-7.35 (m, 2H), 7.62-7.64 (m, 1H), 7.77-7.83 (m, 1H)

elemental analysis (C11H9N2OF)

Calculated: C: 64.70, H: 4.44: N: 13.72, O: 7.84, F: 9.30

Found: C: 64.78, H: 4.43, N: 13.66.

melting point 119.5-122.5 ° C

Example 27 (Reference)

4-naphthalen-2-yl-2- (iminomethyl) -4-oxobutanonitrile

The reaction was carried out by an operation similar to that of Example 26 and using (2-naphthalen-2-yl-2-oxoethyl) propanedinitrile (700 mg), and concentrated under reduced pressure. Ethyl acetate (10 ml) was added to the concentrate, and the mixture was stirred for 15 minutes. The crystals were collected by suction filtration, washed with ethyl acetate (2 ml), and dried under reduced pressure at 50 ° C for 2 hours to obtain the title compound (617 mg, 61.2% yield) .

1H-NMR (300 MHz, DMSO-d6) S (ppm): 3.91 (s, 14 / 10H), 3.98 (s, 6 / 10H), 6.40 (brd, J = 11.0 Hz , 14 / 10H), 6.55 (brd, J = 11.2 Hz, 6/10 H), 6.91 (t, J = 11.0 Hz, 7 / 10H), 7.03 (t, J = 11.2 Hz, 3 / 10H), 7.57-7.67 (m, 20 / 10H), 7.91-8.00 (m, 30 / 10H), 8.09 (d, J = 7 , 5 Hz, 10 / 10H), 8.68 (brs, 10 / 10H).

elemental analysis (C15H12N2O)

Calculated: C: 76.25, H: 5.12, N: 11.86, O: 6.77

Found: C: 76.13, H: 5.19, N: 11.77.

melting point 154.0-157.0 ° C

Example 28 (Reference)

4- (4-methoxyphenyl) -2- (iminomethyl) -4-oxobutanonitrile

The reaction was carried out by an operation similar to that of Example 26 and using [2- (4-methoxyphenyl) -2-oxoethyl] propanedinitrile (5.00 g) to obtain the compound of the statement (6.14 g). Ethyl acetate (3 ml) was added to 0.95 g thereof, and the mixture was stirred at room temperature for 0.5 hours. The crystals were collected by suction filtration, washed with ethyl acetate (2 ml), and dried under reduced pressure at 50 ° C for 2 hours to obtain the most purified statement compound (0.24 g).

1H-NMR (300 MHz, DMSO-d6) S (ppm): 3.67 (s, 12 / 7H), 3.73 (s, 2/7H), 3.82 (s, 21 / 7H), 6 , 36 (brd, J = 11.0 Hz, 12 / 7H), 6.45 (brd, J = 11.0 Hz, 2 / 7H), 6.80 (t, J = 11.0 Hz, 6 / 7H), 6.94 (t, J = 11.0 Hz, 1 / 7H), 7.00-7.05 (m, 14 / 7H), 7.93 (d, J = 8.9 Hz, 14 / 7H).

elemental analysis (C12H12N2O2)

Calculated: C: 66.65, H: 5.59, N: 12.96, O: 14.79

Found: C: 66.61, H: 5.44, N: 13.09.

melting point 133.5-134.5 ° C

Example 29 (Reference)

4- (4-methylphenyl) -2- (iminomethyl) -4-oxobutanonitrile

The reaction was carried out by an operation similar to that of Example 26 and using [2- (4-methylphenyl) -2-oxoethyl) propanedinitrile (980 mg) to obtain the above-mentioned compound (867 mg, 87.6 yield %). Ethyl acetate (4 ml) was added thereto, and the mixture was stirred at room temperature for 1 hour. The crystals were collected by suction filtration, washed with ethyl acetate (2 ml), and dried under reduced pressure at room temperature for 2 hours to obtain the most purified statement compound (345 mg).

1H-NMR (300 MHz, DMSO-d6) S (ppm): 2.35 (s, 12 / 4H), 3.70 (s, 6 / 4H), 3.76 (s, 2 / 4H), 6 , 31 (brd, J = 11.1 Hz, 6 / 4H), 6.45 (brd, J = 11.1 Hz, 2 / 4H), 6.81 (t, J = 11.1 Hz, 3 / 4H), 6.94 (t, J = 11.1 Hz, 1 / 4H), 7.30 (d, J = 8.1 Hz, 8 / 4H), 7.85 (d, J = 8.1 Hz, 8 / 4H).

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elemental analysis (C12H12N2O)

Calculated: C: 71.98, H: 6.04, N: 13.99, O: 7.99 Found: C: 71.94, H: 6.08, N: 13.95 melting point 158.0 -160.0 ° C Example 30 (Reference)

4- (2-methylphenyl) -2- (iminomethyl) -4-oxobutanonitrile

The reaction was carried out by an operation similar to that of Example 26 and using [2- (2-methylphenyl) -2-oxoethyl] propanedinitrile (1.00 g). The THF solution was concentrated to dryness under reduced pressure. Ethyl acetate (2 ml) was added thereto, and the mixture was stirred at room temperature for 0.5 hours. The crystals were collected by suction filtration, washed with ethyl acetate (1 ml), and dried under reduced pressure at 50 ° C for 2 hours to obtain the most purified statement compound (498 ml, yield 49.3 %).

1H-NMR (300 MHz, DMSO-d6) S (ppm): 2.39 (s, 15 / 6H), 2.41 (s, 3 / 6H), 3.66 (s, 10 / 6H), 3 , 73 (s, 2 / 6H), 6.37 (brd, J = 11.0 Hz, 10 / 6H), 6.50 (brd, J = 11.0 Hz, 2 / 6H), 6.82 ( t, J = 11.0 Hz, 5 / 6H), 6.96 (t, J = 11.0 Hz, 1 / 6H), 7.27-7.34 (m, 12 / 6H), 7.39 -7.44 (m, 6 / 6H), 7.75 (d, J = 7.7 Hz, 5 / 6H), 7.82 (d, J = 7.8 Hz, 1 / 6H).

elemental analysis (C12H12N2O)

Calculated: C: 71.98, H: 6.04, N: 13.99, O: 7.99

Found: C: 72.06, H: 6.05, N: 14.00

melting point 111.0-114.0 ° C

Example 31 (Reference)

2- (iminomethyl) -4-oxo-4-phenylbutanonitrile

The reaction was carried out by an operation similar to that of Example 29, and using (2-oxo-2- (phenylethyl) propanedinitrile (1.82 g) to obtain the title compound (804 mg, yield 43.7 %).

1H-NMR (300 MHz, DMSO-d6) S (ppm): 3.75 (s, 10 / 8H), 3.81 (s, 6/8), 6.34 (brd, J = 11.0 Hz , 10 / 8H), 6.47 (d, J = 11.0 Hz, 6 / 8H), 6.82 (t, J = 11.0 Hz, 5 / 8H), 6.96 (t, J = 11.0 Hz, 3 / 8H), 7.48-7.56 (m, 16 / 8H), 7.59-7.65 (m, 8 / 8H), 7,947.98 (m, 16 / 8H) .

elemental analysis (C11H10N2O)

Calculated: C: 70.95, H: 5.41, N: 15.04, O: 8.59

Found: C: 70.97, H: 5.34, N: 15.14

melting point 89.0-90.0 ° C

Example 32 (Reference)

5- (4-methylphenyl) -1H-pyrrole-3-carbonitrile

At 4- (4-methylphenyl) -2- (iminomethyl) -4-oxobutanonitrile (217 mg) THF (1 ml) and acetic acid (0.44 ml) were added, and the mixture was reacted at an external temperature of 50 ° C The reaction mixture was extracted with ethyl acetate, and washed successively with aqueous sodium bicarbonate solution and with water. The ethyl acetate was concentrated under reduced pressure. The residue was crystallized from ethyl acetate (1 ml) / n-hexane (7 ml). The crystals were collected by suction filtration, washed with ethyl acetate (0.2 ml) / n-hexane (1.6 ml), and dried under reduced pressure at 45 ° C for 3 hours to obtain the compound of the stated (110 mg, yield 55.7%).

1H-NMR (300 MHz, DMSO-d6) S (ppm): 2.27 (s, 3H), 6.84 (dd, J = 1.6, 2.9 Hz, 1H), 7.18 (d , J = 8.2 Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H), 7.65 (dd, J = 1.6, 2.3 Hz, 1H), 12.13 (brs, 1H).

elemental analysis (C12H10N2)

Calculated: C: 79.10, H: 5.53, N: 15.37

Found: C: 79.00, H: 5.47, N: 15.50.

melting point 169.0-171.0 ° C

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5- (2-fluorophenyl) -1H-pyrrole-3-carbonitrile

[2- (2-fluorophenyl) -2-oxoethyl] propanedinitrile (10.0 g, 49.46 mmol) and THF (95 ml) were weighed, placed in a 200 ml flask and dissolved. The mixture was purged with an inert gas, 5% Pd-C (4.0 g, corresponding to 2 mol% based on Pd) was added, and washed with THF (5 ml). Then, the mixture was purged with hydrogen and reacted at room temperature. The catalytic reduction was enhanced until the starting material reached less than 2%. The catalyst was extracted by filtration, and washed twice with THF (20 ml). The THF solution was concentrated under reduced pressure to approximately 28 g. Acetic acid (20 ml) was added thereto, and the mixture was reacted at an external temperature of 50 ° C for 4 hours.

Water (100 ml) was added dropwise to this reaction mixture. The crystals were allowed to age at room temperature, collected by suction filtration, washed with aqueous ethanol solution (ethanol: water = 1: 4, 20 ml), and dried under reduced pressure at 50 ° C to obtain 5 - (2-fluorophenyl) -1H-pyrrole-3-carbonitrile (7.38 g).

7.00 g of the 5- (2-fluorophenyl) -1 H -pyrrole-3-carbonitrile obtained were suspended in acetic acid (14 ml), and the suspension was stirred at room temperature for 1 hour. The solid was collected by suction filtration, washed with aqueous fna ethanol solution (ethanol: water = 1: 4, 10 ml), and dried under reduced pressure at 50 ° C to obtain 5- (2-fluorophenyl) - 1H-pyrrole-3-carbonitrile (5.96 g, 68.2% yield).

Example 34 (Reference)

5-naphthalen-2-yl-1H-pyrrole-3-carbonitrile

(2-Naphthalen-2-yl-2-oxoethyl) propanedinitrile (2.00 g) was dissolved in THF (50 ml). The mixture was purged with an inert gas, 5% Pd-C (1.2 g) was added, and the mixture was purged with an inert gas. Then, the mixture was purged with hydrogen, and reacted at room temperature for 4.5 hours. Catalytic reduction was performed until the starting material became less than 2%. The catalyst was extracted by filtration, and washed with THF. The filtrate was concentrated under reduced pressure. Acetic acid was added thereto (30 ml), and the mixture was reacted at an external temperature of 50 ° C for 4 hours. Ethyl acetate was added, and the mixture partitioned. The organic layer was washed with water, saturated aqueous sodium bicarbonate and saturated brine, in that order. The organic layer was concentrated under reduced pressure to provide a residue (1.66 g). This was quantified by HPLC to obtain the compound of the statement (1.20 g, 65.8% yield). This was purified by column chromatography (ethyl acetate / n-hexane) to provide the title compound (858 mg, 46.1% yield).

1H-NMR (300 MHz, DMSO-d6) S (ppm): 7.08 (s, 1H), 7.42-7.52 (m, 2H), 7.76-7.93 (m, 5H) , 8.20 (s, 1H), 12.40 (brs, 1H).

melting point 200.5-206.5 ° C Example 35 (Reference)

5- (2,4-dimethoxyphenyl) -1H-pyrrole-3-carbonitrile

The reaction was carried out by an operation similar to that of Example 34 and using [2- (2,4-dimethoxyphenyl) -2-oxoethyl] propanedinitrile (700 mg). Quantification by HPLC gave the compound of the statement (493 mg, 75.4% yield). Purification by column chromatography (ethyl acetate / n-hexane) provided the statement compound (410 mg, 62.7% yield).

1H-NMR (300 MHz, DMSO-d6) S (ppm): 3.77 (s, 3H), 3.85 (s, 3H), 6.57 (d, J = 8.5 Hz, 1H), 6.62 (s, 1H), 6.75 (s, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.56 (s, 1H), 11.68 (brs, 1H ).

elemental analysis (C13H12N2O2)

Calculated: C: 68.41, H: 5.30, N: 12.27, O: 14.02

Found: C: 68.44, H: 5.31, N: 12.43

melting point 129.0-130.0 ° C

Example 36 (Reference)

5- (4-methoxyphenyl) -1H-pyrrole-3-carbonitrile

The reaction was carried out by an operation similar to that of Example 34 and using [2- (4-methoxyphenyl) -2-oxoethyl) propanedinitrile (5.0 g). Quantification by HPLC gave the compound of the statement (3.4 g, 87.3% yield). This was recrystallized from ethyl acetate / n-hexane (1: 2) to provide the

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compound of the statement (3.1 g, yield 80.4%).

1H-NMR (300 MHz, DMSO-da) S (ppm): 3.75 (s, 3H), 6.77 (s, 1H), 6.95 (d, J = (8.7 Hz, 2H) , 7.58 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 0.6 Hz, 1H), 12.07 (brs, 1H).

elemental analysis (C12H10N2O)

Calculated: C: 72.71, H: 5.08, N: 14.13, O: 8.07.

Found: C: 72.48, H: 5.06, N: 14.11.

melting point 185.0-186.0 ° C

Example 37 (Reference)

5- (4-methylphenyl) -1H-pyrrole-3-carbonitrile

The reaction was carried out by an operation similar to that of Example 34 and using [2- (4-methylphenyl) -2-oxoethyl] propanedinitrile (5.0 g). Quantification by HPLC gave the compound of the statement (3.4 g, 73.8% yield).

Example 38 (Reference)

5- (2-methylphenyl) -1H-pyrrole-3-carbonitrile

The reaction was carried out by an operation similar to that of Example 34, and using [2- (2-methylphenyl) -2-oxoethyl] propanedinitrile (1.00 g) to obtain the above-mentioned compound (535 mg, yield of 63.1%).

1H-NMR (300 MHz, DMSO-d6) S (ppm): 2.37 (s, 3H), 6.63 (d, J = 1.4 Hz, 1H), 7.23-7.31 (m , 3H), 7.38-7.41 (m, 1H), 7.71 (d, J = 1.4 Hz, 1H), 11.98 (brs, 1H).

elemental analysis (C12H10N2)

Calculated: C: 79.10, H: 5.53, N: 15.37

Found: C: 78.94, H: 5.55, N: 15.26.

melting point 151.0-152.5 ° C

Example 39 (Reference)

5-phenyl-1H-pyrrole-3-carbonitrile

The reaction was carried out by an operation similar to that of Example 34, and using (2-oxo-2-phenylethyl) propanedinitrile (4.5 g). Quantification by HPLC gave the compound of the statement (2.4 g, yield 58.3%).

1H-NMR (300 MHz, DMSO-d6) S (ppm): 6.92 (dd, J = 1.6, 2.3 Hz, 1H), 7.23-7.26 (m, 1H), 7 , 35-7.40 (m, 2H), 7.65 (s, 1H), 7.64-7.70 (m, 2H), 12.21 (brs, 1H).

elemental analysis (C11H8N2)

Calculated: C: 78.55, H: 4.79, N: 16.66

Found: C: 78.50, H: 4.78, N: 16.69.

melting point 150.0-151.0 ° C

Example 40 (Reference)

5- (4-fluorophenyl) -1 H-pyrrol-3-carbonitrile

The reaction was carried out by an operation similar to that of Example 34 and using [2- (4-fluorophenyl-2- oxoethyl] propanedinitrile (2.00 g). Quantification by HPLC provided the compound of the statement (1.43 g, 77.8% yield).

1H-NMR (300 MHz, DMSO-d6) S (ppm): 6.88 (dd, J = 1.7, 2.2 Hz, 1H), 7.18-7.24 (m, 2H), 7 , 66-7.71 (m, 3H), 12.20 (brs, 1H).

elemental analysis (C11H7N2F)

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Calculated: C: 70.96, H: 3.78, N: 15.04, F: 10.20.

Found: C: 70.99, H: 3.74, N: 15.16. melting point 158.4-159.3 ° C Example 41 (Reference)

5- (4-chlorophenyl) -1H-pyrrole-3-carbonitrile

The reaction was carried out by an operation similar to that of Example 34 and using [2- (4-chlorophenyl) -2-oxoethyl] propanedinitrile (5.0 g). Quantification by HPLC gave the compound of the statement (2.2 g, 48.8% yield).

1H-NMR (300 MHz, DMSO-da) S (ppm): 6.96 (dd, J = 1.6, 2.5 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H ), 7.65 (s, 1H), 7.67 (d, J = 8.7 Hz, 2H), 12.26 (brs, 1H).

elemental analysis (C-n ^^ Cl)

Calculated: C: 65.20, H: 3.47, N: 13.82, Cl: 17.50.

Found: C: 65.45, H: 3.49, N: 13.81.

melting point 174.2-175.1 ° C

Example 42 (Reference)

4- methyl-5-phenyl-1H-pyrrole-3-carbonitrile

The reaction was carried out by an operation similar to that of Example 34 and using (1-methyl-2-oxo-2-phenylethyl) propanedinitrile (1.00 g). Quantification by HPLC gave the compound of the statement (624 mg, 71.1% yield).

1H-NMR (300 MHz, DMSO-d6) S (ppm): 2.23 (s, 3H), 7.27-7.30 (m, 1H), 7.39-7.50 (m, 4H) , 7.59 (d, J = 2.3 Hz, 1H), 11.88 (brs, 1H).

elemental analysis (C12H10N2)

Calculated: C: 79.10, H: 5.53; N: 15.37.

Found: C: 79.02, H: 5.50; N: 15.42.

melting point 130.0-134.5 ° C dec.

Example 43 (Reference)

4,5-diphenyl-1H-pyrrole-3-carbonitrile

The reaction was carried out by an operation similar to that of Example 34 and using (2,2-diphenylethyl-2-oxo) propanedinitrile (1.00 g). Quantification by HPLC gave the compound of the statement (556 mg, yield 45.2%).

1H-NMR (300 MHz, DMSO-d6) S (ppm): 7.10-7.38 (m, 10H), 7.80 (d, J = 3.1 Hz, 1H), 12.21 (brs , 1 HOUR). elemental analysis (C17H12N2)

Calculated: C: 83.58, H: 4.94, N: 11.47.

Found: C: 83.30, H: 5.08, N: 11.33. melting point 163.0-166.0 ° C Example 44 (Reference)

5- tert-butyl-1H-pyrrole-3-carbonitrile

The reaction was carried out by an operation similar to that of Example 34 and using (3,3-dimethyl-2-oxobutyl) propanedinitrile (1.00 g). Quantification by HPLC gave the compound of the statement (682 mg, 75.5% yield). This was further purified by column chromatography (ethyl acetate / n-hexane) to obtain the title compound (0.54 g, 59.4% yield).

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1H-NMR (300 MHz, DMSO-da) S (ppm): 1.20 (s, 9H), 6.07 (dd, J = 2.3, 1.8 Hz, 1H), 7.42 (dd , J = 2.9, 1.8 Hz, 1H), 11.46 (brs, 1H).

elemental analysis (C9H12N2)

Calculated: C: 72.94, H: 8.16, N: 18.90.

Found: C: 72.68, H: 8.24, N: 19.03

melting point 101.5-103.0 ° C.

Example 45 (Reference)

5- (2-fluorophenyl) -1H-pyrrole-3-carbonitrile

N, N-dimethylacetamide (4 ml), [2- (2-fluorophenyl) -2-oxoethyl] propanedinitrile (500 mg, 2.47 mmol) and triethylamine (5.51 g, 54.41 mmol) were added in one flask, and cooled with ice. Formic acid (2.28 g, 49.46 mmol) was added dropwise while paying attention to heat generation. The mixture was heated to room temperature, and purged with an inert gas. 5% Pd-C (N.E. CHEMCAT, 500 mg) was added, and the mixture was reacted at room temperature for 2.5 hours. Acetic acid (2 ml) was added to the reaction mixture, and the mixture was reacted at an external temperature of 50 ° C for 1 hour and 10 minutes. The catalyst was extracted by filtration, and washed with THF (approximately 5 ml). Quantification of the filtrate by HPLC gave the compound of the statement (189 mg, yield 41.0%).

Example 46 (Reference)

Methyl 5- (2-fluorophenyl) -1H-pyrrole-3-carboxylate

Methyl-2-cyano-4- (2-fluorophenyl) -4-oxobutanoate (500 mg, 2.13 mmol) was dissolved in THF (5 ml), and 5% Pd / C (50% wet, 200 was added) mg) Under hydrogen atmosphere, the mixture was stirred at room temperature for 4 hours. The catalyst was extracted by filtration, and washed with THF. The filtrate was concentrated under reduced pressure, THF (10 ml) and acetic acid (10 ml) were added, and the mixture was stirred at room temperature for 1 hour. The quantification of the reaction mixture by HPLC confirmed the production of the compound of the statement (249 mg, 53.5% yield).

1H-NMR (300 MHz, CDCla) S (ppm): 3.85 (3H, s), 7.01-7.27 (4H, m), 7.49-7.65 (2H, m), 9 , 30 (1H, brs). elemental analysis (C12H10NO2F)

Calculated: C: 65.75, H: 4.60, N: 6.39, O: 14.59, F: 8.66 Found: C: 65.46, H: 4.62, N: 6.36 melting point 152.3-152.7 ° C Example 47 (Reference)

[2- (2-fluorophenyl) -2-oxoethyl] propanedinitrile (2.00 g, 9.89 mmol), acetic acid (30 ml) and THF (15 ml) were weighed and dissolved (under argon atmosphere). Next, Raney (0.5 ml) and water (4.5 ml) were weighed and added, and the mixture was purged with hydrogen. This was reacted at room temperature for 8 hours. Quantification of the filtrate by HPLC gave 5- (2-fluorophenyl) -1H-pyrrol-3-carbonitrile (654 mg, yield 35.6%).

Example 48 (Reference)

[2- (2-fluorophenyl) -2-oxoethyl] propanedinitrile (2.00 g, 9.89 mmol), acetic acid (22 ml) and THF (22 ml) were weighed and dissolved (under argon atmosphere). Then Raney (0.5 ml) and water were weighed and added, and the mixture was purged with hydrogen. This was reacted at room temperature for about 9 hours. Quantification of the filtrate by HPLC gave 5- (2-fluorophenyl) -1H-pyrrol-3-carbonitrile (831 mg, yield 45.2%).

Example 49 (Reference)

[2- (2-fluorophenyl) -2-oxoethyl] propanedinitrile (2.00 g, 9.89 mmol), acetic acid (6 ml) and THF (22 ml) were weighed and dissolved (under argon atmosphere). Then Raney (0.5 ml) and water (4.5 ml) were weighed and added, and the mixture was purged with hydrogen. This was reacted at room temperature for about 9 hours. Quantification of the filtrate by HPLC gave 5- (2-fluorophenyl) -1H-pyrrole-3-carbonitrile (682 mg, 37.1% yield).

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[2- (2-fluorophenyl) -2-oxoethyl] propanedinitrile (2.00 g, 9.89 mmol), N, N-dimethylformamide (10 ml) and ammonium format (3.2 g) were weighed and dissolved (under argon atmosphere). Next, 5% Pd-C (600 mg) was added, and the mixture was reacted at room temperature for about 1 hour, and at an external temperature of 50 ° C for about 2 hours. The catalyst was extracted by filtration, and the filtrate was quantified by HPLC to provide 5- (2-fluorophenyl) -1H-pyrrol-3-carbonitrile (0.089 g, yield 9.70%).

Example 51 (Reference)

[2- (2-fluorophenyl) -2-oxoethyl] propanedinitrile (2.00 g, 9.89 mmol) and formic acid (6 ml) were weighed and dissolved (under argon atmosphere). Then Raney (0.5 ml) and water (4.5 ml) were weighed and added, and the mixture was purged with hydrogen. 5% Pd-C (600 mg) was added, and the mixture was reacted at an external temperature of 50 ° C for about 5 hours (triethylamine (0.2 ml), formic acid (3 ml) and Pd- 5% C (600 mg) were added during the reaction). The catalyst was extracted by filtration, and the filtrate was quantified by HPLC to give 5- (2-fluorophenyl) -1H-pyrrol-3-carbonitrile (230 mg, 24.9% yield).

Example 52 (Reference)

[2- (2-fluorophenyl) -2-oxoethyl] propanedinitrile (2.00 g, 9.89 mmol), acetic acid (22 ml) and THF (22 ml) were weighed and dissolved (under argon atmosphere). Next, Raney (1 ml) and water (2 ml) were weighed and added, and the mixture was purged with hydrogen. This was reacted at 45-50 ° C for about 5 hours. Quantification of the filtrate by HPLC gave 5- (2-fluorophenyl) -1H-pyrrol-3-carbonitrile (718 mg, 38.6% yield) and 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldelmdo ( 277 mg, yield 14.8%).

Example 53 (Reference)

2,2'-disulfanodiylbis [5- (2-methylphenyl) -1H-pyrrole-3-carbonitrile]

To a slurry of [2- (2-methylphenyl) -2-oxoethyl] propanedinitrile obtained in Reference Example 4 and methanol, thioacetic acid (66.6 ml, 932 mmol), triethylamine (13.0 ml, 93 , 2 mmol) and dimethyl sulfoxide (8.59 ml, 121 mmol), and the mixture was heated under reflux at the internal temperature of about 60 ° C for 13 hours. The reaction mixture was gradually cooled to 30 ° C or less, further cooled to an internal temperature of 5 + 5 ° C and stirred for 1 hour. The precipitated crystals were collected by filtration, and washed with cold ethanol (62.5 ml). The wet crystals were dried under reduced pressure at 50 ° C to obtain the title compound (56.4 g, 57% yield) as yellow crystals.

melting point 248.0-249.0 ° C

1H-NMR (300 MHz, DMSO-d6) S (ppm): 12.7 (s, 2H), 7.41 (d, J = 6.0 Hz, 2H), 7.31-7.26 (m , 6H), 6.78 (d, J = 2.4 Hz, 2H), 2.40 (s, 6H).

elemental analysis (C24H18N4S2)

Calculated: C, 67.58; H, 4.25; N, 13.13; S, 15.03.

Found: C, 67.40; H, 4.20; N, 13.04; S, 14.92.

LC-MS: 426 [M +]

Example 54 (Reference)

5- (2-methylphenyl) -1H-pyrrole-3-carbonitrile

Raney (139 g), N, N-dimethylformamide (300 ml) and morpholine (15.5 ml, 178 mmol) were added in a four-mouth flask, and the mixture was stirred under a stream of nitrogen at room temperature. While maintaining the internal temperature at 40 ° C or less, a solution of 2,2'-disulfanodiylbis [5- (2-methylphenyl) -1H-pyrrole-3-carbonitrile] (50g, 117 mmol) in N was slowly added , N-dimethylformamide (150 ml), drop by drop. The drip funnel was washed with N, N-dimethylformamide (50 ml). The mixture was heated under reflux at an internal temperature of 100-110 ° C for 1.5 hours. After cooling to room temperature, the Raney nickel was filtered off, and the residue was washed with ethyl acetate (150 ml). Ethyl acetate (350 ml) and 10% brine (750 ml) were added to the filtrate for extraction and distribution. The aqueous layer was extracted with ethyl acetate (250 ml, 125 ml, 125 ml). The organic layers were combined, washed with water (1 L) and concentrated to approximately half of the amount under reduced pressure. Ethanol (250 ml) was added to the concentrate, and the mixture was concentrated to approximately 241 g. This operation was repeated 3 times. Water (250 ml) was added while stirring the concentrate with heating at 75-85 ° C, and the mixture was further stirred at the same temperature for 1 hour. The mixture was gradually cooled to no more than 30 ° C, further cooled to the internal temperature of 5 + 5 ° C, and stirred for 1 hour. The precipitated crystals were collected by filtration, and washed with a cold mixture of ethanol (37.5 ml) and water (37.5 ml). The wet crystals were dried under reduced pressure at 50 ° C until they were

5

10

fifteen

twenty

25

30

35

40

Four. Five

achieved a constant weight to obtain the compound of the statement (35.5 g, 83% yield). melting point 151-152 ° C.

1H-NMR (300 MHz, DMSO-da) S (ppm): 2.37 (s, 3H), 6.61 (d, J = 1.36 Hz, 1H), 7.23-7.31 (m , 3H), 7.38-7.41 (m, 1H), 7.71 (d, J = 1.36 Hz, 1H), 11.98 (brs, 1H).

elemental analysis (C12H10N2)

Calculated: C, 79.09; H, 5.52; N, 15.37.

Found: C, 78.94; H, 5.55; N, 15.26.

Example 55 (Reference)

S- [3-Cyano-5- (2-methylphenyl) -1H-pyrrole-2-yl] benzenecarbonitrile

[2- (2-Methylphenyl) -2-oxoethyl] propanedinitrile (10 g, 50.4 mmol), thiobenzoic acid (11.2 g, 81.0 mmol), triethylamine (508 mg, 5.04 mmol) were mixed and methanol (100 ml), and the mixture was stirred at approximately 60 ° C for about 3 hours. Water (10 ml) was added at about 35 ° C, and the mixture was stirred at room temperature for 1 hour, and at about 10 ° C for about 1 hour. The precipitated crystals were collected by filtration, and washed with a mixture of methanol (24 ml) and water (6 ml). The wet crystals were dried under reduced pressure to obtain the title compound (14.4 g, 90% yield).

1H-NMR (300 MHz, DMSO-d6) S (ppm): 2.40 (s, 3H), 6.90 (s, 1H), 7.28-7.30 (m, 3H), 7.40 -7.43 (m, 1H), 7.65 (t, J = 7.6 Hz, 2H), 7.78-7.80 (m, 1H), 8.02-8.05 (m, 2H ), 12.6 (brs, 1H)

Example 56 (Reference)

5- (2-methylphenyl) -1H-pyrrole-3-carbonitrile

Raquel (73 g), N, N-dimethylformamide (150 ml) and morpholine (13.0 ml, 149 mmol) were added in a four-mouth flask, and the mixture was stirred under a stream of nitrogen at room temperature. While maintaining the internal temperature at 40 ° C or lower, a solution of S- [3-cyano-5- (2-methylphenyl) -1H-pyrrole-2-yl] benzenecarbonitrile (31.6 g, 99) was slowly added , 2 mmol) in N, N-dimethylformamide (130 ml), dropwise. The drip funnel was washed with N, N-dimethylformamide (30 ml). The mixture was heated under reflux at the internal temperature of 100-110 ° C for 1.5 hours. After cooling to room temperature, the Raney nickel was extracted by filtration, and the residue was washed with ethyl acetate (210 ml). Ethyl acetate (210 ml) and 10% brine (750 ml) were added to the filtrate for extraction and distribution. The aqueous layer was extracted with ethyl acetate (150 ml, 75 ml, 75 ml). The organic layers were combined, washed with water (210 ml) and concentrated under reduced pressure. Ethanol (212 ml) was added to the concentrate, and the mixture was concentrated to about 204 g. This operation was repeated 3 times. Water (210 ml) was added while stirring the concentrate with heating at 75-85 ° C, and the mixture was further stirred at the same temperature for 1 hour. The mixture was gradually cooled to no more than 30 ° C, further cooled to an internal temperature of 5 + 5 ° C, and stirred for 1 hour. The precipitated crystals were collected by filtration, and washed with a cold mixture of ethanol (4.5 ml) and water (10.5 ml). The wet crystals were dried under reduced pressure at 50 ° C until a constant weight was achieved to obtain the statement compound (14.1 g, 78% yield).

Example 57 (Reference)

5- (2-methylphenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbonitrile

5- (2-methylphenyl) -1H-pyrrole-3-carbonitrile (35.0 g, 192 mmol), acetonitrile (131 ml), 4-N, N-dimethylaminopyridine (4.69 g, 38.4 mmol) and Diisopropylethylamine (269 mmol, 46.1 ml) was added in a four-mouth flask, and the mixture was stirred at room temperature. While maintaining the internal temperature at 40 ° C or lower, a solution of 3-pyridinosulfonyl chloride (40.9 g, 230 mmol) in acetonitrile (37 ml) was slowly added dropwise, the dropping funnel was washed with acetonitrile (7 ml). The mixture was reacted at room temperature for 1 hour, and tap water 87.5 ml) was added to the reaction mixture. 0.5 N HCl was added dropwise to adjust the pH to 4.5, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, and washed with a mixture of acetonitrile (21.2 ml) and water (21.2 ml). The wet crystals were dried under reduced pressure at 50 ° C to obtain the title compound (54.8 g, 90% yield).

1H-NMR (300 MHz, CDCla) S (ppm): 8.81 (d, J = 1.8 Hz, 1H), 8.52 (d, J = 1.8 Hz, 1H), 8.01 ( s, 1H), 7.60-7.56 (br, 1H), 7.38-7.18 (m, 4H), 6.88 (d, J = 7.5 Hz, 1H), 6.56 (s, 1H), 1.82 (s, 3H).

5- (2-Methylphenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldel'ndo hydrochloride.

5- (2-Methylphenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-carbonitrile (123.6 mmol, 40.0 g), tetrahydrofuran (160 ml), acetic acid (240 ml) were added ), water (240 ml) and Raney (32.0 g) in a four-mouth flask, and the mixture was reacted under hydrogen slightly under pressure at 17-25 ° C for 9 hours. After completion of the reaction, the catalyst was extracted by filtration, and washed with a mixture of tetrahydrofuran (15 ml), acetic acid (22.5 ml) and water (22.5 ml). The filtrate was extracted with ethyl acetate (400 ml) and tap water (400 ml). The organic layer was washed twice with tap water (200 ml), and partitioned. The organic layer was concentrated under reduced pressure to approximately 60 g, ethyl acetate (200 ml) was added to the concentrate, and the mixture was concentrated again under reduced pressure to approximately 60 g. This operation was performed twice in total. Ethyl acetate (300 ml) was added to adjust the amount of liquid to approximately 330 g. To the ethyl acetate solution was added slowly, dropwise, 4 N ethyl acetate / chloro acid solution (62 ml, 247 mmol) at 25-35 ° C. After completion of the dropwise addition, the mixture was stirred at an internal temperature of 50-55 ° C for 1 hour. The suspension was cooled to 20-30 ° C, and stirred at the same temperature for 1 hour, and then 15 to 0-10 ° C for 1 hour. The precipitated crystals were collected by filtration, and washed with ethyl acetate (80 ml). The wet crystals were dried under reduced pressure at 50 ° C until a constant weight was achieved to obtain the statement compound (38 g, 85% yield).

1H-NMR (500 MHz, DMSO-d6) S (ppm): 1.74 (s, 3H), 6.58 (d, J = 1.58 Hz, 1H), 6.83-6.91 (m , 1H), 7.11-7.25 (m, 2H), 7.38 (td, J = 7.57, 1.26 Hz, 1H), 7.62 (dd, J = 8.20, 4 , 73 Hz, 1H), 7.85-7.94 (m, 1H), 8.47 (d, J = 1.89 Hz, 1H), 8.56 20 (d, J = 1.58 Hz, 1H), 8.91 (dd, J = 4.73, 1.58 Hz, 1H), 9.90 (s, 1H), 1H was not detected.

Example 59 (Reference)

N-methyl-1- [5- (2-methylphenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl] methanamine fumarate

Under a stream of nitrogen, 40% methylamine methanol solution 21.2 ml, 207 mmol) and methanol (60 ml) were added in a four-mouth flask, and a 5- (2-methylphenyl hydrochloride solution was added ) -1- (pyridin-3-25 ylsulfonyl) -1H-pyrrole-3-carbaldehyde (30 g, 82.7 mmol) in N, N-dimethylformamide (90 ml), drop by drop, at 30 ° C or less . The mixture was stirred at about 25 ° C for 1 hour, Na2CO3 (8.76 g, 82.7 mmol) was added, and the mixture was further stirred for 1 hour. The mixture was cooled with ice to 0-5 ° C, a solution of sodium borohydride (1.56 g, 41.3 mmol) in N, N-dimethylformamide (30 ml) was slowly added dropwise. 10 ° C or less. The mixture was stirred at 0-5 ° C for 1 hour, 2N chlortudric acid (200 ml) was added dropwise at 15 ° C or less 30 to adjust the pH to 2, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (300 ml) and 12.5% aqueous ammonia (180 ml) were added, and the mixture was stirred at room temperature for 30 minutes and partitioned. The aqueous layer was extracted with ethyl acetate (180 ml). The organic layers were combined, washed with 5% brine (180 ml) and partitioned. The organic layer was concentrated to 40 g, ethyl acetate (300 ml) was added and the mixture was concentrated again. This operation was carried out twice, and the mixture was concentrated to a total amount of 165 g, N, N-dimethylformamide (150 ml) was added to the concentrated residue, and the mixture was heated to the internal temperature of 50-60 ° C. 9.6 g, 82.7 mmol) was added. The mixture was stirred at the internal temperature of 50-60 ° C for 30 minutes, allowed to cool and stirred at 20-30 ° C for 1 hour, and stirred further at 010 ° C for 1 hour. The precipitated crystals were collected by filtration, and washed with a cold mixture of N, N-dimethylformamide (30 ml) and ethyl acetate (30 ml). The wet crystals were dried under reduced pressure 40 to 50 ° C until a constant weight was reached to obtain the title compound as a crude product (24.5 g, 65% yield).

1H-NMR (300 MHz, DMSO-d6) S (ppm): 8.88-8.86 (m, 1H), 8.44 (s, 1H), 7.81-7.78 (m, 1H) , 7.67 (s, 1H), 7.61-7.56 (m, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.21-7.12 (m, 2H ), 6.84 (d, J = 6.7 Hz, 1H), 6.47 (s, 2H), 6.32 (s, 1H), 3.85 (s, 2H), 2.43 (s , 3H), 1.81 (s, 3H), 1H not detected.

45 elementary analysis (C22H23N3O6S)

Calculated: C, 57.76; H, 5.07; N, 9.18; S, 7.01; Or, 20.98.

Found: C, 57.87; H, 5.03; N, 9.24; S, 7.00.

A crude product (100 g) of N-methyl-1- [5- (2-methylphenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl] methanamine fumarate and 10% hydrated methanol ( 900 ml), were added in a four-mouth flask, and the mixture was dissolved by heating. The insoluble material was extracted by filtration, and washed with 10% hydrated methanol (100 ml). The filtrate was heated again to reflux temperature, and stirred for 30 minutes. After cooling to 40-45 ° C, the mixture was stirred at the same temperature for 1 hour, at room temperature for 16 hours, and also at 10 ° C or less for 1 hour. The precipitated crystals were collected by filtration, and washed with 50% cold hydrated methanol (100 ml). The wet crystals were dried under reduced pressure at 50 ° C until a constant weight was achieved to obtain the statement compound (72 g, 72% yield).

[2- (2-Methylphenyl) -2-oxoethyl] propanedinitrile (30 g, 151.3 mmol), thiobenzoic acid (28.5 ml, 243 mmol), triethylamine (2.1 ml, 15.1 mmol) were mixed and methanol (300 ml), and stirred at approximately 60 ° C for about 4-5 hours. Water (30 ml) was added at approximately 36 ° C, and the mixture was stirred at approximately 10 ° C for about 2 hours. The precipitated crystals were collected by filtration, and washed with a mixture of methanol (72 ml) and water (18 ml). The wet crystals were dried under reduced pressure to obtain the title compound (44.2 g, 91.7% yield).

Example 61 (Reference)

10 5- (2-methylphenyl) -1H-pyrrole-3-carbonitrile

Miquel Raney (92 g), water (100 ml), N, N-dimethylacetamide (200 ml) and morpholine (16.4 ml, 187.1 mmol) were mixed. A solution of S- [3-cyano-5- (2-methylphenyl) -1H-pyrrol-2-yl] benzenecarbonitrile (40.0 g, 125.6 mmol) in N, N-dimethylacetamide (200 ml) was added. , drop by drop, to the mixture at room temperature. After stirring at about 100 ° C for about 3 hours, the mixture was cooled to 30 ° C under a stream of nitrogen. The Raney nickel was extracted by filtration and ethyl acetate (400 ml) was added to the filtrate. The mixture was washed with 10% aqueous sodium chloride solution (646 ml) and with water (580 ml). The organic layer was concentrated under reduced pressure to about one fifth, ethanol (141 ml) was added, and the mixture was concentrated to about 134 ml. Water (188 ml) was added dropwise at about 80 ° C, and the mixture was stirred at about 5 ° C for about 2 hours. The precipitated crystals were collected by filtration, and washed with a mixture of ethanol (35 ml) and water (47 ml). The wet crystals were dried under reduced pressure to obtain the title compound (20.9 g, 87.1% yield).

Example 62 (Reference)

5- (2-methylphenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbonitrile

5- (2-methylphenyl) -1H-pyrrole-3-carbonitrile (18.0 g, 98.8 mmol), acetonitrile (67 ml), diisopropylethylamine (23.7 ml, 138 mmol) and 4-N, N -dimethylaminopyridine (2.41 g, 19.7 mmol) were mixed. A solution of 3-pyridinosulfonyl chloride (21.3 g, 118 mmol) in acetonitrile (23 ml) was added dropwise at approximately 30 ° C. The mixture was stirred at room temperature for about 3 hours, water (50 ml) was added dropwise, and 0.5 N hydrochloric acid was added dropwise to adjust the pH to 4. The precipitated crystals were collected by filtration. , washed with a mixture of acetonitrile (11 ml) and water (11 ml). The wet crystals were dried under reduced pressure to obtain the title compound (25.8 g, 80.7% yield).

Example 63 (Reference)

5- (2-Methylphenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde hydrochloride.

Under a stream of nitrogen, water (60 ml), acetic acid (60 ml), tetrahydrofuran (40 ml), 5- (2- methylphenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3 were mixed -carbonitrile (10.0 g) and mquel Raney (8 g). The mixture was stirred at approximately 25 ° C and an internal hydrogen pressure of 0.001 - 0.008 MPa for about 10 hours. After the completion of the reaction, Raney was extracted by filtration, and washed with a mixture of tetrahydrofuran (3.8 ml), acetic acid (5.6 ml) and water (5.6 ml). To the filtrate and the washing products, ethyl acetate (100 ml) and water (100 ml) were added for the partition, and the organic layer was concentrated under reduced pressure. Ethyl acetate (50 ml) was added, and the mixture was concentrated under reduced pressure to approximately 83 g. A solution of ethyl acetate / 4N hydrochloric acid (15 ml) was added dropwise at room temperature, and the mixture was stirred at about 50 ° C for about 1 hour, and about 10 ° C for about 1 hour. The precipitated crystals were collected by filtration, and washed with ethyl acetate (20 ml). The wet crystals were dried under reduced pressure to obtain the title compound (9.5 g, 85% yield).

Example 64 (Reference)

45 N-methyl-1- [5- (2-methylphenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl] methanamine fumarate

5- (2-Methylphenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde hydrochloride (20.0 g, 55.1 mmol), ethyl acetate (200 ml) and water (60 ml) were mixed and partitioned. The organic layer was concentrated under reduced pressure. N, N-dimethylacetamide (60 ml) was added, and a mixture of 40% methylamine methanol solution (14.3 ml) and methanol (120 ml) was added dropwise at about 10 ° C. a mixture of sodium borohydride (834 mg) and N, N-50 dimethylacetamide (20 ml) was added dropwise at about -2 ° C. 4 N hydrochloric acid was added dropwise at about 3 ° C to adjust the pH around 2. Ethyl acetate (240 ml), water (190 ml) and 25% aqueous ammonia (80 ml) were added ) for the partition, and the organic layer was washed with 5% brine (110 ml) and water (104 ml). The organic layer was concentrated under reduced pressure, N, N-dimethylformamide (40 ml) and smoking acid (6.40 g) were added, and the mixture was stirred at approximately 60 ° C for about 3 hours. It was added

ethyl acetate (80 ml) at room temperature, and the mixture was stirred at about 5 ° C for about 3 hours. The precipitated crystals were collected by filtration, and washed with ethyl acetate (120 ml). The wet crystals were dried under reduced pressure to obtain the title compound as a crude product (16.7 g, 65.7% yield).

To a crude product (15.0 g) of the above compound, 20% hydrated methanol (120 ml) was added, and the mixture was dissolved by heating. Activated carbon was added, and the mixture was stirred at about 60 ° C for about 10 minutes. The activated carbon was extracted by filtration, and purified water (200 ml) was added at approximately 30 ° C. After stirring for about 2 hours, the mixture was stirred at about 10 ° C for about 1 hour. The precipitated crystals were collected by filtration, washed with 50% hydrated methanol (60 ml). The wet crystals were dried under reduced pressure, and the dried crystals were pulverized to obtain the title compound (13.0 g, 86.7% yield).

Industrial applicability

The sulfonylpyrrole compound (VIII) obtained by the method of the present invention is useful as an acid secretion inhibitor (proton pump inhibitor).

fifteen

Claims (2)

1.- A method of producing a compound represented by the formula image 1 wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterodyl group, and R2 is a hydrogen atom, an optionally substituted alkyl group, an acyl group, a hydroxy group optionally substituted, an optionally substituted amino group, a chlorine atom or a fluorine atom, or a salt thereof, which comprises reducing a compound represented by the formula image2 10 reduced. 2.- A method of producing a compound represented by the formula image3 wherein R1 and R2 are as defined in claim 1, R3 is an optionally substituted hydrocarbon group or an optionally substituted heterodyl group, and R4 is an alkyl group, or a salt thereof, which comprises: (I) the method according to claim 1, and further comprising, (II) reacting the compound obtained with a compound represented by the formula R3-SO2-X (V) wherein R3 is as defined above and X is a labile group, or a salt thereof, to provide a compound represented by the formula image4 where each symbol is as defined above, or a salt thereof, and (III) reacting the compound obtained with a compound represented by the formula R4-NH2 (VII) 5 wherein R4 is as defined above, or a salt thereof, in the presence of a reducing agent.